EP4683661A2

EP4683661A2 - Anti-medin immunotherapy for vascular aging and related dementias

Info

Publication number: EP4683661A2
Application number: EP24775746.1A
Authority: EP
Inventors: Raymond Migrino; Ming Li; Jillian MADINE
Original assignee: University of Liverpool; US Department of Veterans Affairs
Current assignee: University of Liverpool; US Department of Veterans Affairs
Priority date: 2023-03-23
Filing date: 2024-03-22
Publication date: 2026-01-28
Also published as: WO2024197208A3; WO2024197208A2

Abstract

In one aspect, the invention relates to synthetic medin peptides, derivatives thereof, and related peptides, which are useful as therapeutic agents for disrupting medin toxicity; synthetic methods of making the peptides; pharmaceutical compositions comprising the peptides, and methods of treating, reducing or preventing vascular dy sfunction, cognitive dysfunction, neurodegeneration, neurovascular pathyology, coronary artery disease and/or ischemic heart disease using the disclosed synthetic medin peptides and compositions thereof.

Description

ANTI-MEDIN IMMUNOTHERAPY FOR VASCULAR AGING AND RELATED

DEMENTIAS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/491,799, filed March 23, 2023, entitled “ANTI-MEDIN IMMUNOTHERAPY FOR VASCULAR AGING AND RELATED DEMENTIAS,’’ the entire disclosure of which is hereby incorporated by reference in its entirety.

REFERENCE TO A SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (37559_0496PlSL.xml; Size; 92,709 bytes; and Date of Creation: March 21, 2024) is herein incorporated by reference in its entirety⁷.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0003] This invention was made with government support under 101 BX003767-05 awarded by the Department of Veterans Affairs and 1R21AG075543-01 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0004] Age is the most important risk factor for cardio-cerebrovascular diseases (CVD) and dementia disorders (1, 25). Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with dementia disorders, including Alzheimer’s disease (AD) and AD-related dementias (ADRD) such as vascular dementia (VaD) (2, 3). Indeed, unbiased data-driven analyses showed that vascular dysfunction is the earliest and strongest brain pathology⁷ associated with late onset AD (4).

[0005] There is growing evidence that medin. a 50-amino acid peptide that forms one of the most common yet least studied human amyloidosis (5), is an important driver of vascular aging pathologies (6). Vascular medin burden is associated with VaD (7, 8), AD (7) and aortic aneurysms (9-12). Medin, a cleavage product of milk fat globule-EGF factor 8 protein (MFGE8), accumulates in vessels with aging (5, 13-18), causes endothelial dysfunction through oxidative and nitrative stress (19, 20) and induces endothelial pro-inflammatory activation that could initiate neuroinflammation (8, 20). Cerebrovascular medin accumulation in aged (20 month old) C57BL/6 mice, and importantly, selective knockout of medin- containing domain in MFGE8 gene prevented cerebrovascular dysfunction in aged mice (21). Modified peptide F(BA)S (22) and monosialoganglioside-containing nanoliposomes (23) disrupt medin aggregation and prevent medin-induced endothelial cytotoxicity and pro- inflammatory activation.

[0006] Although the molecular, functional and structural changes of vascular aging have been described (26), the causative mediators of intrinsic vascular aging remain unknown. Vascular aging and inflammation start decades before onset of clinical manifestations. Autopsies of young soldiers or young heart donors show that vascular inflammation starts at a young age (27-30), with prevalence of 17% in teenagers rising to >70% by age 40 (29). It is critical to change our treatment paradigm and intervene early to prevent development of vascular aging phenotype that leads to vascular disease and neurodegeneration.

[0007] What is needed are compositions and methods for reducing or disrupting medin toxicity and treating or ameliorating symptoms of vascular disease and neurodegeneration. Also needed are compositions and methods for attenuating medin-induced vascular dysfunction or neurovascular pathology as well as modulating medin aggregation.

BRIEF SUMMARY

[0008] Described herein are compositions and methods for reducing or disrupting medin toxicity and treating or ameliorating symptoms of vascular disease and neurodegeneration. Also described herein are compositions and methods for attenuating medin-induced vascular dysfunction or neurovascular pathology as well as modulating medin aggregation.

[0009] Disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0010] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the carrier epitope is at the N terminus of the peptide.

[0011] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide is at the C-terminus of the peptide.

[0012] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[0013] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[0014] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form

[0015] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[0016] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[0017] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[0018] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[0019] Also disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form, wherein the carrier epitope is KLH.

[0020] Also disclosed herein are nucleic acid molecules capable of encoding the peptides disclosed herein. Also disclosed herein are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [0021] Also disclosed herein are vectors comprising one or more of the nucleic acid molecules disclosed herein. Also disclosed are vectors comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0022] Also disclosed herein are cells comprising one or more of the peptides, nucleic acid molecules or vectors disclosed herein. Disclosed herein are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0023] Disclosed herein are cells comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0024] Disclosed herein are cells comprising a vector, wherein the vector comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [0025] Disclosed herein are compositions comprising one or more of the peptides, nucleic acid constructs, vectors or cells disclosed herein. Disclosed herein are compositions comprising a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [0026] Disclosed herein are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0027] Disclosed herein are compositions comprising a vector comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0028] Disclosed herein are compositions comprising a cell, wherein the cell comprises a vector, wherein the vector comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0029] Also disclosed herein are pharmaceutical compositions comprising one or more of the peptides, nucleic acid constructs, vectors, cells or compositions disclosed herein.

Disclosed herein are pharmaceutical compositions comprising a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and a pharmaceutically acceptable carrier.

[0030] Disclosed herein are pharmaceutical compositions comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and a pharmaceutically acceptable carrier. [0031] Disclosed herein are pharmaceutical compositions comprising a vector, wherein the vector comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and a pharmaceutically acceptable carrier.

[0032] Disclosed herein are pharmaceutical compositions comprising a cell, wherein the cell comprises a vector, wherein the vector comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and a pharmaceutically acceptable carrier.

[0033] Disclosed herein are pharmaceutical compositions comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and a pharmaceutically acceptable carrier.

[0034] Disclosed herein are methods of disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein. [0035] Disclosed herein are methods of reversing medin induced endothelial activation in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0036] Disclosed herein are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein. [0037] Disclosed herein are methods of vaccinating a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0038] Disclosed herein are methods of attenuating medin-induced vascular dysfunction or neurovascular pathology' in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0039] Disclosed herein are methods of modulating vascular disease in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein. [0040] Disclosed herein are methods of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein. [0041] Disclosed herein are methods of treating or preventing vascular dysfunction or inflammation induced by medin in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0042] Disclosed herein are methods of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0043] Disclosed herein are methods of modulating or preventing cerebrovascular dysfunction, cognitive dysfunction, neurodegeneration and/or neurovascular pathology in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0044] Disclosed herein are methods of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0045] Disclosed herein are methods of reducing the rate of grow th of amyloid plaques in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

[0046] Disclosed herein are methods of treating coronary artery disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects of the disclosed method and compositions and together with the description, serve to explain the principles of the disclosed method and compositions.

[0048] FIG. 1 describes a scheme for inhibiting medin-induced toxicity .

[0049] FIGs. 2A-2F shows that cerebrovascular medin is higher in AD. FIG. 2A shows medin deposits (brown DAB) in elderly brain artenoles. FIG. 2B shows higher arteriole medin score in AD versus non-demented (ND) donors. FIG. 2C shows higher arteriole medin seen in donors with more neurofibrillary' tangles (Braak stage) and higher Ap plaque density⁷ score (FIG. 2D). FIG. 2E shows AUC-ROC analysis shows arteriole medin and cerebral amyloid angiopathy (CAA), but not circle of Willis (CoW) atherosclerosis score, are highly predictive of AD diagnosis. FIG. 2F shows that among vascular pathologies, arteriole medin has the highest odds ratio for AD diagnosis.

[0050] FIGs. 3A-3E show medin causes cerebrovascular dy sfunction in aging wild-ty pe mice. FIG. 3 A shows schematic structure of human and C57BL/6J mouse Mfge8 gene showing major protein domains including medin component (left), amino acid sequence comparison of human medin with homologous mouse sequence and TANGO prediction of aggregation-prone peptides within the medin sequence with high conservation but lower aggregation propensity in mouse (right). FIG. 3B shows that in aged (20 month old) but not young (2 month old) mice, medin aggregate-like structures are present in brain vasculature (white arrows) and directly correlate with age (FIG. 3C). Medin knockout (FIG. 3 A, bottom) prevented cerebrovascular medin aggregation in aging mice (FIG. 3B, bottom panel), and using in vivo 2 photon imaging following hindlimb stimulation (FIG. 3D), normalized vessel dilation time of responsiveness compared to aged mice (FIG. 3E). [0051] FIGs. 4A-4L show that medin induces endothelial dysfunction, oxidative stress and inflammatory’ activation. FIG. 4A shows ex-vivo human collateral cerebral arteries exposed to medin (5 pM, 1 hour) show impaired dilator response to acetylcholine (endothelial dysfunction). FIGs. 4B-4D show that this effect is due to oxidative and nitrative stress with medin causing increased arteriole superoxide (FIG. 4C) and peroxynitrite (FIG. 4D) production and reduced NO (FIG. 4B) The effects were reversed by antioxidant PEG-SOD (data not shown). FIGs. 4E-4I show in human endothelial cells. 20 hr. medin exposure increased activated NFKB with increased pro-inflammatory activation as seen with increased IL-8, IL-6, ICAM-1 and PALL These changes were reversed by NFKB inhibitor (data not shown). FIGs. 4J-4L show' 3D chip with astrocytes in central (green) chamber and either ECs or no ECs in side chambers (red). Astrocyte production of IL-8 was higher when ECs are present following exposure to medin, suggesting paracrine-type modulation of glial inflammation by endothelial activation induced by medin.

[0052] FIG. 5 is a picture of a western blot using primary’ monoclonal antibodies purified from C57BL/6 mice immunized with KLH-C-T’-QGARD-F'-GHIQYVA (medin fragment): the Western blot showed that the mAb following immunization had great ability to attach/conjugate with medin fragment (lane 5), purified recombinant human medin (lane 2) and medin polypeptides in human umbilical vein endothelial cells (lane 3).

[0053] FIGs. 6A-6B show ICAM-1 (FIG. 6A) or VCAM-1 (FIG. 6B) gene expression in human brain endothelial cells in vitro when mixed with medin and monoclonal antibodies extracted from C57BL/6 mice immunized with KLH-C-T’-QGARD-F’-GHIQYVA (medin fragment). This shows that following immunization with KLH-C-T’-QGARD-F’- GHIQYVA, the resulting monoclonal antibody produced showed ability⁷ to suppress endothelial activation and inflammation in endothelial cells induced by medin.

[0054] FIGs. 7A-B shows that medin is present in cerebral artery of 12 month (FIG. 7B) but not 2 month old (FIG. 7A) SAMP8 mouse (using anti-medin antibody). SAMP8 is a mouse model of premature aging.

[0055] FIG. 8 shows a schematic showing the experimental design for medin vaccine efficacy testing.

[0056] FIGs. 9A-9D show medin in coronary arteries following post-mortem histology of elderly brain and body donors. FIG. 9A show coronary⁷ artery⁷ from donor who had myocardial infarction (MI) and diabetes and tissue did not receive anti-medin primary⁷ antibody, thus serving as tissue control. FIGs. 9B-C show coronary arteries from donors who had MI and diabetes and stained with anti-medin primary antibody (DAB staining); blue/brown/black stain (sample regions in black arrows) denotes medin which is found in tunica intima (endothelial layer), tunica media (smooth muscle layer) and tunica adventitia of the coronary arteries. Note the blood clot in the lumen of the coronary artery that caused the myocardial infarction in FIG. 9A. FIG. 9D shows prominent medin accumulation in endothelial cells and in smooth muscle layer of coronary⁷ artery of a diabetic patient. The figure indicates that coronary⁷ artery disease is accompanied by coronary arterial medin deposit! on/accumulati on.

[0057] FIGs. 10A-10B show effects of polyclonal antibodies against medin derived from medin immunization. FIG. 10A shows that following immunization of rabbits with human medin, polyclonal antibodies targeting three epitopes of medin were created. FIG. 10B shows that when human endothelial cells were treated with medin, there was increased pro- inflammatory⁷ gene expression (IL-8 (left), IL-6 (center) and IL- 1 [3 (right)), and the pro- inflammatory⁷ effect of medin was reduced when medin was co-treated with polyclonal antibodies derived from medin vaccination of rabbits.

DETAILED DESCRIPTION

[0058] The disclosed method and compositions may be understood more readily by reference to the following detailed description of particular aspects and the Examples included therein and to the Figures and their previous and following description.

[0059] It is to be understood that the disclosed method and compositions are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, may vary⁷. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

A. Definitions

[0060] The terminology⁷ used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0061] As used in the specification and the appended claims, the singular forms “a,” “an⁷’ and “the’⁷ can include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes mixtures of compounds, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.

[0062] The word “of⁷ as used herein means any one member of a particular list and also includes any combination of members of that list. [0063] Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0064] As used herein, the term “amino acid sequence” refers to a list of abbreviations, letters, characters or words representing amino acid residues. The amino acid abbreviations used herein are conventional one letter codes for the amino acids and are expressed as follows: A. alanine; C, cysteine; D aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K. lysine; L, leucine; M, methionine; N, asparagine; P. proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; and Y, tyrosine. All alpha amino acids except glycine can exist in either of two enantiomers, called L-amino acids or D-amino acids, which are mirror images of each other.

[0065] As used herein, the term “amino acid” refers to an organic molecule with a basic amino group (-NH2), an acidic carboxyl group (-COOH), a proton and a variable ‘R’ group bound to an sp3 hybridized central carbon atom. The N-terminus of a peptide has a free amino group (-NH2). The C-terminus of a peptide has a free carboxyl group (-COOH). [0066] As used herein, the terms “D-amino acid” or “amino acid in the D-form” refer to amino acids where the stereogenic carbon alpha to the amino group has the D-configuration. A “D-amino acid” is the enantiomer of an amino acid that is capable of rotating plane polarized light clockwise (right-hand side). D-amino acids are designated with the prime (’) symbol.

[0067] As used herein, the terms “L-amino acid” or “amino acid in the L-form” refer to amino acids where the stereogenic carbon alpha to the amino group has the L-configuration. L amino acid is the enantiomer of an amino acid that is capable of rotating plane polarized light anticlockwise (left-hand side). With the exception of achiral glycine, natural amino acids have the L configuration.

[0068] “Peptide” as used herein refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein. A peptide is comprised of consecutive amino acids. The term “peptide” encompasses naturally occurring or synthetic molecules. A residue of a peptide is an amino acid. As used herein if an amino acid is said to be in the 5^th position, it is the 5^th amino acid from the N-terminus of the peptide.

[0069] By “fragment” is meant a portion of a polypeptide or nucleic acid molecule, such as, but not limited to, a truncation mutant. This portion contains, preferably, at least about 5%, 10%. 20%. 30%. 40%. 50%. 60%. 70%. 80%. 90%. 95% of the entire length of the reference nucleic acid molecule or polypeptide. For example, a fragment of a polypeptide may contain about 5, about 10, about 15, about 20, about 25 or about 30 or more amino acids. In another example, a fragment of a polypeptide may contain about 1000, about 1500, about 2000, about 2500 or about 3000 or more amino acids.

[0070] As used herein, the term “epitope” refers to a localized region on the surface of an antigen capable of eliciting an immune response.

[0071] As used herein, the term “carrier epitope” refers to an inactive, accessory substance used as a vehicle to deliver a vaccine to a subject. Non-limiting examples of carrier epitopes include KLH, N19 poly epitope, CRM 197. diphtheria toxoid (DT), tetanus toxoid (TT). Haemophilus protein D (PD), the outer membrane protein complex of serogroup B meningococcus (OMPC), BSA (bovine serum albumin) , OVA (ovalbumin), beta glucosidase and haptens.

[0072] As used herein, “KLH” refers to keyhole limpet hemocyanin (“KLH”) which is a large, multisubunit, oxygen-carrying, metalloprotein that is found in the hemolymph of the giant keyhole limpet, Megathura crenulata. KLH is an effective carrier protein for several reasons. Its large size and numerous epitopes generate a substantial immune response, and abundance of lysine residues for coupling haptens allows a high hapten: carrier protein ratio, increasing the likelihood of generating hapten-specific antibodies. KLH may also refer to a fragment of KLH.

[0073] As used herein, “sample” is meant to mean an animal; a tissue or organ from an animal: a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (e.g. a polypeptide or nucleic acid), which is assayed as described herein. A sample may also be any body fluid or excretion (for example, but not limited to, blood, urine, stool, saliva, tears, bile) that contains cells or cell components. [0074] As used herein, “subject’' refers to the target of administration, e.g. an animal. Thus the subject of the disclosed methods can be a vertebrate, such as a mammal. For example, the subject can be a human. The term does not denote a particular age or sex. Subject can be used interchangeably with “individual” or “patient”.

[0075] As used herein, “modulate” is meant to mean to alter, by increasing or decreasing. [0076] As used herein, “isolated polypeptide” or “purified polypeptide” is meant to mean a polypeptide (or a fragment thereof) that is substantially free from the materials with which the polypeptide is normally associated in nature. The polypeptides of the invention, or fragments thereof, can be obtained, for example, by extraction from a natural source (for example, a mammalian cell), by expression of a recombinant nucleic acid encoding the polypeptide (for example, in a cell or in a cell-free translation system), or by chemically synthesizing the polypeptide. In addition, polypeptide fragments may be obtained by any of these methods, or by cleaving full length proteins and/or polypeptides.

[0077] “Dose” or “dosage” as used herein refers to a specific quantity⁷ of a therapeutic agent, such as a peptide, that is taken at specific times.

[0078] As used herein, “treat” is meant to mean administer one of the disclosed compositions to a subject, such as a human or other mammal (for example, an animal model), that has atherosclerosis, in order to prevent or delay a worsening of the effects of the disease or condition, or to partially or fully reverse the effects of the disease.

[0079] As used herein, “prevent” is meant to mean minimize the chance that a subject will develop medin toxicity, medin-induced endothelial activation, medin -induced vascular dysfunction, medin-induced neurovascular pathology, vascular disease, medin aggregation, vascular dysfunction, inflammation, cerebrovascular dysfunction, cognitive dysfunction, neurodegeneration, neurovascular pathology, amyloid plaque formation, coronary artery disease and/or ischemic heart disease.

[0080] As used herein, the term “treatment cycle” refers to the administration of a peptide for an established period of time. A treatment cycle includes a wide range of dosages of peptide as well as different lengths of time for administering one or more ofthe peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein. For example, a treatment cycle can be a three month period wherein one of the peptides disclosed herein is administered twice a week for the three month period.

[0081] As used herein, “effective amount” is meant to mean a sufficient amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed herein to provide the desired effect. For example, an effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed hereincan be an amount that provides a therapeutic affect and provides sustained therapeutic effects after withdrawal of the treatment. An effective amount of one or more of the peptides, nucleic acid constructs, vectors, cells, compositions or pharmaceutical compositions disclosed hereincan be an amount that is able to cause a benefit illustrated by a disruption or decrease in medin toxicity, a reversal of medin-induced endothelial activation, an induction of an immune response, a modulation, reduction or prevention of vascular disease, a modulation, reduction or prevention of medin aggregation, treating, reducing or preventing vascular dysfunction or inflammation, reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) and/or plasminogen activator inhibitor-1 (PAI-1), modulating, reducing or preventing amyloid plaque formation, reducing the rate of growth of amyloid plaques, as well as an amount that allows for a sustained therapeutic effect after withdrawal of the peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of disease (or underlying genetic defect) that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate “effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.

[0082] As used herein, “sustained therapeutic effect” is a therapeutic effect that persists after the therapeutic has been withdrawn. For example, the sustained therapeutic effect is maintained even after the acute disruption in medin toxicity⁷ is gone.

[0083] The phrase “nucleic acid” as used herein refers to a naturally occurring or synthetic oligonucleotide or polynucleotide, whether DNA or RNA or DNA-RNA hybrid, singlestranded or double-stranded, sense or antisense, which is capable of hybridization to a complementary nucleic acid by Watson-Crick base-pairing. Nucleic acids of the invention can also include nucleotide analogs (e.g., BrdU), and non-phosphodiester intemucleoside linkages (e g., peptide nucleic acid (PNA) or thiodiester linkages). In particular, nucleic acids can include, without limitation, DNA, RNA, cDNA, gDNA, ssDNA, dsDNA or any combination thereof.

[0084] The terms “vector” or “construct” refer to a nucleic acid sequence capable of transporting into a cell another nucleic acid to which the vector sequence has been linked. The term "expression vector" includes any vector, (e.g., a plasmid, cosmid or phage chromosome) containing a gene construct in a form suitable for expression by a cell (e.g., linked to a transcriptional control element). "Plasmid" and "vector" are used interchangeably, as a plasmid is a commonly used form of vector. Moreover, the invention is intended to include other vectors which serve equivalent functions.

[0085] The term “expression vector” is herein to refer to vectors that are capable of directing the expression of genes to which they are operatively-linked. Common expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. Recombinant expression vectors can comprise a nucleic acid as disclosed herein in a form suitable for expression of the acid in a host cell. In other words, the recombinant expression vectors can include one or more regulatory elements or promoters, which can be selected based on the host cells used for expression that is operatively linked to the nucleic acid sequence to be expressed.

[0086] As used herein, “disrupting medin toxicity” means a decrease or reduction in any medin-mediated effect on a subject, including, but not limited to, medin-induced endothelial actiation, medin-induced vascular dysfunction or vascular disease, medin-induced neurovascular pathology, medin-induced inflammation, medin-induced modulation of IL-8, IL-6, ICAM-1 and/or PAI-1, medin-induced cerebrovascular dysfunction, medin-induced cognitive dysfunction, medin-induced neurodegeneration, medin-induced neurovascular pathology', medin-induced amyloid plaque formation, medin-induced coronary artery' disease and/or medin-induced ischemic heart disease.

[0087] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed method and compositions belong. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present method and compositions, the particularly useful methods, devices, and materials are as described. Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. No admission is made that any reference constitutes prior art. The discussion of references states what their authors assert, and applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of publications are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art. B. Compositions

1. Peptides

[0088] Non-limiting examples of the peptides of the disclosure are provided herein. Disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide.

[0089] Disclosed herein are peptides comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[0090] In some aspects, the fragment of SEQ ID NO: 1 can be SEQ ID NO: 3, SEQ ID NO:

5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO:

27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37 or SEQ ID NO: 39.

[0091] In some aspects, the fragment of SEQ ID NO: 2 can be SEQ ID NO: 4, SEQ ID NO:

6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO:

28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38 or SEQ ID NO:40.

[0092] In some aspects, no more than 7 consecutive amino acids of the modified medin peptide or fragment thereof are in the L-form. In some aspects, no more than 6 consecutive amino acids of the modified medin peptide or fragment thereof are in the L-form. In some aspects, no more than 5 consecutive amino acids of the modified medin peptide or fragment thereof are in the L-form. In some aspects, no more than 4 consecutive amino acids of the modified medin peptide or fragment thereof are in the L-form.

[0093] In some aspects, the modified medin peptide or fragment thereof has at least one amino acid in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least two amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least three amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least four amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least five amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least six amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least seven amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least eight amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least nine amino acids in the D-form. In some aspects, the modified medin peptide or fragment thereof has at least ten amino acids in the D- form.

[0094] In some aspects, the modified medin peptide is SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64. SEQ ID NO: 65. SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77 or SEQ ID NO: 78.

[0095] In some aspects, the carrier epitope is at the N terminus of a peptide. In some aspects, the carrier epitope is at the C-terminus of a peptide.

[0096] In some aspects, the modified medin peptide or fragment thereof is at the C-terminus of the peptide. In some aspects, the modified medin peptide or fragment thereof is at the N- terminus of the peptide.

[0097] In some aspects, the modified medin peptide or fragment thereof is from 10 to 25 amino acids long. In some aspects, the modified medin peptide or fragment thereof is from 12 to 18 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 10 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 11 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 12 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 13 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 14 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 15 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 16 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 17 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 18 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 19 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 20 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 21 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 22 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 23 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 24 amino acids long. In some aspects, the modified medin peptide or fragment thereof is 25 amino acids long.

[0098] In some aspects, the disclosed peptides can be made synthetically or recombinantly. In some aspects, the disclosed peptides can be conjugated to a carrier protein (e.g. conjugated to KLH using methods such as maleimide method).

Table 1 - Medin peptides

Table 2 - Modified Medin Peptides

[0099] Also contemplated are peptides that do not comprise one or more amino acids at the C-terminal end of SEQ ID NO: 1 or SEQ ID NO: 2. For example, contemplated are peptides which do not comprise the C-terminal amino acid (Alanine; A) of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last two amino acids (Valine and Alanine; V-A) of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last three amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last four amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last five amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last six amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last seven amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last eight amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last nine amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last ten amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last eleven amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last twelve amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last thirteen amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last fourteen amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. Also contemplated are peptides which do not comprise the last fifteen amino acids of SEQ ID NO: 1 or SEQ ID NO: 2. [00100] Also contemplated are peptides having the sequences set forth above that have a D- amino acid in locations not specifically identified in Table 1 and Table 2 above. D-amino acids are designated with the prime (’) symbol. For example, disclosed are petides comprising any of the sequences of SEQ ID NO: 1 through SEQ ID NO. 78. Also contemplated are peptides having D-amino acids in any location(s) in the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, as long as the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. 2. Variants

[00101] Also disclosed a variants or derivatives of the peptides disclosed herein. Nonlimiting examples of the peptides have been described herein (see Tables 1-2, for example). As used herein, the term “analog” is used interchangeably with “variant” and “derivative.” Variants and derivatives are well understood to those of skill in the art and can involve amino acid sequence modifications. Such amino acid sequence modifications typically fall into one or more of three classes: substantial; insertional; or deletional variants. Insertions include amino and/or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily are smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. These variants ordinarily are prepared by site-specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example Ml 3 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final derivative or analog. Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with Tables 3 and 4 and are referred to as conservative substitutions.

[00102] Substantial changes in function or immunological identity are made by selecting substitutions that are less conservative than those in Table 3, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties are those in which: (a) the hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl or alanyl; Tryptophan, Tyrosinyl (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or hystidyl, is substituted for (or by) an electronegative residue, e.g. glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, or (e) by increasing the number of sites for sulfation and/or glycosylation. Table 3 Amino Acid Substitutions

Table 4: Amino Acid Abbreviations

[00103] It is understood that one way to define the variants and derivatives of the disclosed proteins herein is to define them in terms of homology/identity to specific known sequences. Specifically disclosed are variants of peptides herein disclosed which have at least, 70% or at least 75% or at least 80% or at least 85% or at least 90% or at least 95% or at least 96% or at least 97% or at least 98% or at least 99% identity to the peptides specifically recited herein. Those of skill in the art readily understand how to determine the identity of two proteins. [00104] The polypeptides can be modified by either natural processes, such as post- translational processing, or by chemical modification techniques which are well known in the art. Modifications can occur anywhere in the polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. The same type of modification can be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide can have many types of modifications. Modifications include, without limitation, acetylation, acylation, ADP-ribosylation, amidation, covalent cross-linking or cyclization, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of a phosphytidylinositol, disulfide bond formation, demethylation, formation of cysteine or pyroglutamate, fonnylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristolyation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, and transfer-RNA mediated addition of amino acids to protein such as arginylation. (See Proteins - Structure and Molecular Properties 2nd Ed., T.E. Creighton, W.H. Freeman and Company, New York (1993); Posttranslational Covalent Modification of Proteins, B.C. Johnson, Ed., Academic Press, New York, pp. 1-12 (1983)).

3. Nucleic Acids

[00105] As this specification discusses various peptide sequences it is understood that the nucleic acids that can encode those polypeptide sequences are also disclosed. This would include all degenerate sequences related to a specific polypeptide sequence, i.e. all nucleic acids having a sequence that encodes one particular polypeptide sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed polypeptide sequences.

[00106] Disclosed are nucleic acid molecules capable of encoding any of the peptides described herein. For example, disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00107] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00108] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide. [00109] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00110] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00111] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form.

[00112] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00113] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00114] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00115] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8). [00116] Disclosed are nucleic acid molecules capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

4. Vectors

[00117] Disclosed are vectors comprising a nucleic acid molecule capable of encoding any of the peptides disclosed herein.

[00118] For example, disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00119] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00120] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00121] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00122] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00123] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the ammo acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form.

[00124] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00125] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00126] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00127] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8). [00128] Disclosed are vectors comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

[00129] Vectors that can be used herein can include plasmids, cosmids, and viruses (e.g., bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). Vectors can comprise targeting molecules. A targeting molecule is one that directs the desired nucleic acid to a particular organ, tissue, cell, or other location in a subject's body. A vector, generally, brings about replication when it is associated with the proper control elements (e.g., a promoter, a stop codon, and a polyadenylation signal). Examples of vectors that are routinely used in the art include plasmids and viruses. The term “vector” includes expression vectors and refers to a vector containing a nucleic acid sequence coding for at least part of a gene product capable of being transcribed. A variety of ways can be used to introduce an expression vector into cells. In some aspects, the expression vector comprises a virus or an engineered vector derived from a viral genome. As used herein, “expression vector” is a vector that includes a regulatory region. A variety' of host/expression vector combinations can be used to express the nucleic acid sequences disclosed herein. Examples of expression vectors include but are not limited to plasmids and viral vectors derived from, for example, bacteriophages, retroviruses (e.g., lentiviruses), and other viruses (e.g., adenoviruses, poxviruses, herpesviruses, baculovirus, tobacco mosaic virus and adeno- associated viruses). Vectors and expression systems are commercially available and known to one skilled in the art.

5. Cells

[00130] As this specification discusses various peptide sequences and nucleic acid constructs, it is understood that cells comprising peptides and/or the nucleic acid constructs that can encode those polypeptide sequences are also disclosed.

[00131] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00132] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00133] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00134] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00135] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00136] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00137] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00138] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00139] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00140] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the ammo acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00141] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form.

[00142] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the ammo acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form. [00143] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00144] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00145] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00146] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00147] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6)

[00148] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00149] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8). [00150] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8). [00151] Disclosed are cells comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

[00152] Disclosed are cells comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein. Examples of cells include, but are not limited to endothelial cells, smooth muscle cells, neurons, astrocytes, microglia, oligodendrocytes, immortalized cell lines such as HEK393 and cancer cell lines.

6. Compositions

[00153] Dislcosed herein are compositon comprising the peptides, nucleic acid constructs, vectors and cells disclosed hererin. For example, disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00154] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00155] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00156] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00157] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00158] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00159] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00160] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide.

[00161] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00162] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00163] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00164] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide is at the C-terminus of the peptide.

[00165] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00166] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00167] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00168] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

[00169] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00170] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00171] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00172] Disclosed are compositions comprising cells, wherein the cells comprise a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

[00173] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form. [00174] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the ammo acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form.

[00175] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form.

[00176] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3) and wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form.

[00177] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00178] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00179] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00180] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00181] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00182] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00183] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00184] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00185] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00186] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00187] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the ammo acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6). [00188] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

[00189] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00190] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8). [00191] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00192] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

[00193] Disclosed are compositions comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

[00194] Disclosed are compositions comprising nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

[00195] Disclosed are compositions comprising cells, wherein the cells comprise a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

[00196] Disclosed are compositions comprising cells, wherein the cells comprise nucleic acid molecules capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form and wherein the carrier epitope is at the N terminus of the peptide, wherein the carrier epitope is a KLH protein.

7. Pharmaceutical Compositions

[00197] Disclosed are pharmaceutical compositions comprising any of the peptides, nucleic acid molecules, vectors, cells and compositions disclosed herein and a pharmaceutically acceptable carrier.

[00198] By “pharmaceutically acceptable” is meant a material or carrier that would be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. Examples of carriers include dimyristoylphosphatidyl (DMPC), phosphate buffered saline or a multivesicular liposome. For example, PG:PC:Cholesterol:peptide or PC:peptide can be used as carriers in this invention. Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Other examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline. Ringer's solution and dextrose solution. The pH of the solution can be from about 5 to about 8, or from about 7 to about 7.5. Further carriers include sustained release preparations such as semi-permeable matrices of solid hydrophobic polymers containing the composition, which matrices are in the form of shaped articles, e.g., films, stents (which are implanted in vessels during an angioplasty procedure), liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. [00199] Pharmaceutical compositions can also include carriers, thickeners, diluents, buffers, preservatives and the like, as long as the intended activity of the polypeptide, peptide, nucleic acid, vector of the invention is not compromised. Pharmaceutical compositions may also include one or more active ingredients (in addition to the composition of the invention) such as antimicrobial agents, anti-inflammatory' agents, anesthetics, and the like. The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated.

[00200] Preparations of parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as. for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

[00201] Formulations for optical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. [00202] Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders may be desirable. Some of the compositions may potentially be administered as a pharmaceutically acceptable acid- or baseaddition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mon-, di-, trialkyl and aryl amines and substituted ethanolamines.

C. Methods 1. Methods For Disrupting Medin Toxicity

[00203] Disclosed herein are methods of disrupting medin toxicity in a subject in need thereof comprising administering any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions to the subject. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8. [00204] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00205] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00206] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a cell, wherein the cell comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00207] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00208] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00209] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00210] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00211] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00212] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00213] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00214] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises : a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00215] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises : a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00216] Disclosed herein are methods for disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

2. Methods of Reversing Medin Induced Endothelial Activation

[00217] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering to the subject an effective amount of any one of the peptides, nucleic acids, cells, compositions or pharmaceutical compositions disclosed herein to the subject. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00218] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00219] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00220] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises : a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00221] Disclosed are methods of reversing medin-induced endothelial activation in a subj ect in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00222] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00223] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00224] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00225] Disclosed are methods of reversing medin-induced endothelial activation in a subj ect in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00226] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00227] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00228] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00229] Disclosed are methods of reversing medin-induced endothelial activation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00230] Disclosed are methods of reversing medin-induced endothelial activation in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. 3. Methods of Inducing an Immune Response

[00231] Disclosed are methods of inducing an immune response in a subject in need thereof comprising administering to the subject an effective amount of any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00232] In one embodiment, disclosed are methods of inducing an immune response in a subj ect in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00233] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprisies: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00234] In one embodiment, disclosed are methods of inducing an immune response in a subj ect in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00235] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00236] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00237] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00238] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00239] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00240] In one embodiment, disclosed are methods of inducing an immune response in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00241] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00242] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00243] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00244] In one embodiment, disclosed are methods of inducing an immune response in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

4. Methods of Vaccinating

[00245] Disclosed are methods of vaccinating a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8. [00246] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00247] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00248] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00249] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00250] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00251] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00252] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00253] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00254] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8. [00255] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00256] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00257] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8. [00258] In one embodiment, disclosed is a method of vaccinating a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

5. Methods for Attenuating Medin-Induced Vascular Dysfunction or Neurovascular Pathology

[00259] Disclosed are methods of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00260] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00261] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00262] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00263] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00264] In one embodiment, disclosed is a method of atenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00265] In one embodiment, disclosed is a method of atenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00266] In one embodiment, disclosed is a method of atenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide. wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00267] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00268] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00269] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00270] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00271] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00272] In one embodiment, disclosed is a method of attenuating medin-induced vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

6. Methods for Modulating Vascular Disease

[00273] Disclosed are methods of modulating vascular disease in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00274] In one embodiment, disclosed is a method of modulating vascular disease in a subj ect in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00275] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00276] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00277] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00278] In one embodiment, disclosed is a method of modulating vascular disease in a subj ect in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00279] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00280] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00281] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00282] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00283] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00284] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00285] In one embodiment, disclosed is a method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00286] In one embodiment, disclosed is a method of modulating vascular disease in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

7. Methods for modulating Medin Aggregation

[00287] Disclosed are methods of modulating medin aggregation in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00288] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00289] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00290] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00291] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00292] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00293] In one embodiment, disclosed is a method of modulating medin aggregation in a subj ect in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00294] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00295] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00296] In one embodiment, disclosed is a method of modulating medin aggregation in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00297] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00298] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00299] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00300] In one embodiment, disclosed is a method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

8. Methods for Treating or Preventing Vascular Dysfunction or Inflammation [00301] Disclosed are methods of preventing vascular dysfunction in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00302] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subj ect in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00303] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00304] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00305] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subj ect in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00306] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00307] In one embodiment, disclosed is a method of preventing vascular dy sfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00308] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subj ect in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00309] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00310] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00311] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00312] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00313] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00314] In one embodiment, disclosed is a method of preventing vascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00315] Disclosed are methods of preventing vascular inflammation in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, cells, compositions or pharmaceutical compositions.

[00316] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00317] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00318] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00319] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00320] In one embodiment, disclosed is a method of preventing vascular inflammation in a subj ect in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00321] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00322] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00323] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00324] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00325] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00326] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00327] In one embodiment, disclosed is a method of preventing vascular inflammation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00328] In one embodiment, disclosed is a method of preventing vascular inflammation in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

9. Methods for Reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule- 1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1)

[00329] Disclosed are methods of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, cells, vectors, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00330] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administenng an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00331] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00332] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00333] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00334] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00335] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00336] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00337] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administenng an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00338] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administenng an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00339] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00340] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00341] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-! (PAI-1) levels in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00342] In one embodiment, disclosed is a method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PALI) levels in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00343] In some aspects, the reducing is compared in the same subject before and after administration of the peptides disclosed herein. In some aspects, the reducing is compared to a similarly situated subject.

10. Methods for Modulating or Preventing Cerebrovascular Dysfunction, Cognitive Dysfunction, Neurodegeneration and/or Neurovascular Pathology

[00344] Disclosed are methods of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00345] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00346] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00347] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00348] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00349] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00350] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00351] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00352] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00353] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00354] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00355] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherin the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00356] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00357] In one embodiment, disclosed is a method of modulating or preventing cerebrovascular dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00358] Disclosed are methods of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, cells, compositions or pharmaceutical compositions. [00359] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an ammo acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00360] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00361] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00362] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00363] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00364] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00365] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00366] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00367] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00368] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00369] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an ammo acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00370] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00371] In one embodiment, disclosed is a method of modulating or preventing cognitive dysfunction in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00372] Disclosed are methods of modulating or preventing neurodegeneration in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, cells, compositions or pharmaceutical compositions.

[00373] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00374] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00375] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a cell, wherein the cell comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00376] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00377] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00378] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00379] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00380] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00381] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00382] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00383] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00384] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00385] In one embodiment, disclosed is a method of modulating or preventing neurodegeneration in a subj ect in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00386] Disclosed are methods of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, cells, compositions or pharmaceutical compositions. [00387] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00388] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00389] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology' in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00390] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00391] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00392] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology' in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00393] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00394] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00395] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00396] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00397] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00398] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00399] In one embodiment, disclosed is a method of modulating or preventing neurovascular pathology in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

11. Methods for Modulating or Preventing Amyloid Plaque Formation and/or Reducing the Rate of Growth of Amyloid Plaques

[00400] Disclosed are methods of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00401] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00402] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00403] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00404] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00405] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00406] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00407] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00408] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00409] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00410] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide. wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00411] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00412] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00413] In one embodiment, disclosed is a method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00414] Disclosed are methods of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering to the subject an effective amount any one of the disclosed peptides, nucleic acids, cells, compositions or pharmaceutical compositions.

[00415] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00416] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00417] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a cell comprising a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00418] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a cell comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00419] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00420] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00421] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00422] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the ell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00423] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00424] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00425] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00426] In one embodiment, disclosed is a method of reducing the rate of grow th of amyloid plaque in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00427] In one embodiment, disclosed is a method of reducing the rate of growth of amyloid plaque in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

12. Methods of Treating Coronary Heart Disease and/or Ischemic Heart Disease [00428] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering any one of the disclosed peptides, nucleic acids, vectors, cells, compositions or pharmaceutical compositions to the subject. In some aspects, the method generates an immune response in said subject. In some aspects, the method generates an immune response specific to the peptide. In some aspects, the immune response to the peptide does not generate an immune response or minimal immune response to MFGE8.

[00429] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00430] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00431] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a cell, wherein the cell comprises a nucleic acid molecule capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00432] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00433] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00434] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00435] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00436] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises: a) a earner epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00437] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. [00438] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a nucleic acid capable of encoding a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00439] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises : a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00440] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a cell, wherein the cell comprises a peptide, wherein the peptide comprises : a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

[00441] Disclosed herein are methods of treating coronary heart disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a composition, wherein the composition comprises a peptide, wherein the peptide comprises: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form. 13. Dosing Regimens

[00442] Disclosed are dosing regimens comprising at least one treatment cycle of an effective amount of any of the disclosed peptides, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compositions. The amino acid sequence of the peptide can be, but is not limited to, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11. SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37 and/or SEQ ID NO: 39.

[00443] The modified medin peptide can be, but is not limited to, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75 and/or SEQ ID NO: 77.

[00444] Disclosed herein is are dosing regimens in which the peptide, nucleic acid molecules, cells, compositions or pharmaceutical compsitions is administered only once. [00445] Disclosed herein are dosing regimend in which the peptide, nucleic acid molecules, cells, compositions or pharmaceutical compsitions is administered multiple times over a period of time.

[00446] Treatment cycles can include the administration of different dosages of peptide, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compsitions as well as administration at different time points. The peptides, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compsitions can be administered for varying amounts of time for up to 6 months. The peptide, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compositions can be administered for varying amounts of time indefinitely. In some instances, the administration can occur for up to one, two. three, four, five or six months. For example, the peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can be administered once a week for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks. In some aspects the disclosed peptides, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compositions can be administered about every 3, about every 6 or about every 12 months.

[00447] The length of time for each treatment cycle can vary depending on the amount of peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition administered per dosage. A treatment cycle can include the administration of peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition once, twice or three times a week. In some aspects, the peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can be administered daily. In some aspects, the peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can be administered once every two weeks or even once a month. In some instances, the peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22. or 24 weeks. For example, the treatment cycle can include administering a peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition once a week for four weeks or once every’ two weeks for up to six months. Thus, each treatment cycle includes an established length of time for administration as well as an established dosing schedule during that time frame.

[00448] In one aspect, more than one peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can be administered during the treatment cycles. The more than one peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can be formulated together or in separate compositions. In some instances, one or more peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition is administered in combination with one or more other therapeutic agents, including, but not limited to antibodies, nanobodies, aptamers, liposomes, antioxidants, anti-inflammatory agents, senolytic agents.

14. Dose

[00449] The dose or dosage of peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition can vary depending on many’ factors, such as but not limited to, age, condition, sex and extent of the disease in the patient, route of administration, length of treatment cycle, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.

[00450] Effective dosages can be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the disease is treated. For example, the dosage can be an amount effective to provide therapeutic effects and provide or allow for sustained therapeutic effects even after the treatment (i.e. peptide) is withdrawn. The therapeutic effects can be, but are not limited to, a disruption or decrease in medin toxicity, a reversal of medin-induced endothelial activation, an induction of an immune response, a modulation, reduction or prevention of vascular disease, a modulation, reduction or prevention of medin aggregation, treating, reducing or preventing vascular dysfunction or inflammation, reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) and/or plasminogen activator inhibitor- 1 (PAI-1), modulating, reducing or preventing amyloid plaque formation, reducing the rate of growth of amyloid plaques. The therapeutic effects can be measured by markers of such as, but not limited to, interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) and/or plasminogen activator inhibitor-1 (PAI- 1). Other biomarkers used to measure therapeutic effects can be markers of vascular function, markers of cognitive function, markers of inflammation, such as cytokines, chemokines and/or adhesion molecules), markers of oxidative stress, and/or markers of cell death/apoptosis. The therapeutic effects can be measured by imaging techniques, including MRI, intravascular ultrasound, ultrafast imaging CT scans, B-mode ultrasonography, virtual histology intravascular ultrasound, optical coherence tomography, or other known methods. [00451] The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. The dosage can be adjusted by the individual physician in the event of any counter-indications. Dosage can vary⁷, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[00452] Suitable dosages include, but are not limited to amounts between 0.01 mg/kg and 20 mg/kg. For example, disclosed herein are methods involving administering one or more of the disclosed peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition to a subject, wherein the peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the peptide can be 0.01, 0. 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.

[00453] The peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition dose can be administered as a bolus injection or as an infusion over one or more hours.

15. Delivery

[00454] In the methods described herein, administration or delivery' of the peptides, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compositions can be via a variety of mechanisms. As defined above, disclosed herein are methods of treating, dosing regimens and methods of using those dosing regimens to treat. The dosing regimens and methods include compositions containing any one or more of the polypeptides or nucleic acids described herein that can also include a carrier such as a pharmaceutically acceptable carrier. For example, disclosed are pharmaceutical compositions, comprising the peptides. nucleic acid molecules, vectors, cells and compositions disclosed herein, and a pharmaceutically acceptable carrier.

[00455] The disclosed peptides, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compositions can be in solution or in suspension (for example, incorporated into microparticles, liposomes, or cells). These compositions can be targeted to a particular cell type via antibodies, receptors, or receptor ligands. One of skill in the art knows how to make and use such targeting agents with the disclosed compositions. A targeting agent can be a vehicle such as an antibody conjugated liposomes; receptor mediated targeting of DNA through cell specific ligands, and highly specific retroviral targeting of cells in vivo. Any such vehicles can be part of the compositions herein. For example, targeting agents that direct the peptide, nucleic acid molecule, vector, composition or pharmaceutical composition to a medin peptide, medin polypeptide, or a medin amyloid can be included in the compositions.

[00456] Any suitable route of administration can be used for the disclosed compositions. Suitable routes of administration can, for example, include topical, enteral, local, systemic, or parenteral. For example, administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, inj ection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavemosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracistemal, epidural, peridural, intravitreal, etc. The disclosed compositions can be used in and with any other therapy.

[00457] Nevertheless, in certain aspects, peptide delivery can be enhanced by the use of protective excipients. This is typically accomplished either by complexing the polypeptide with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in an appropriately resistant carrier such as a liposome. Means of protecting polypeptides for oral delivery' are well known in the art (see, e.g., U.S. Pat. No. 5,391,377 describing lipid compositions for oral delivery of therapeutic agents).

[00458] Elevated serum half-life can be maintained by the use of sustained-release protein "packaging" systems. Such sustained release systems are well known to those of skill in the art. In one preferred embodiment, the ProLease biodegradable microsphere delivery' system for proteins and peptides (Tracy (1998) Biotechnol. Prog., 14: 108; Johnson et al. (1996) Nature Med. 2: 795; Herbert et al. (1998). Pharmaceut. Res. 15. 357) a dry powder composed of biodegradable polymeric microspheres containing the active agent in a polymer matrix that can be compounded as a dry formulation with or without other agents.

[00459] The ProLease microsphere fabrication process was specifically designed to achieve a high encapsulation efficiency while maintaining integrity of the active agent. The process consists of (i) preparation of freeze-dried drug particles from bulk by spray freeze-drying the drug solution with stabilizing excipients, (ii) preparation of a drug-polymer suspension followed by sonication or homogenization to reduce the drug particle size, (iii) production of frozen drug-polymer microspheres by atomization into liquid nitrogen, (iv) extraction of the polymer solvent with ethanol, and (v) filtration and vacuum drying to produce the final dry- powder product. The resulting powder contains the solid form of the active agents, which is homogeneously and rigidly dispersed within porous polymer particles. The polymer most commonly used in the process, poly(lactide-co-glycolide) (PLG), is both biocompatible and biodegradable.

[00460] Encapsulation can be achieved at low temperatures (e.g., -40° C.). During encapsulation, the protein is maintained in the solid state in the absence of water, thus minimizing water-induced conformational mobility of the protein, preventing protein degradation reactions that include water as a reactant, and avoiding organic-aqueous interfaces where proteins may undergo denaturation. A preferred process uses solvents in which most proteins are insoluble, thus yielding high encapsulation efficiencies (e.g., greater than 95%).

[00461] In another embodiment, one or more components of the solution can be provided as a "concentrate", e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water.

[00462] The foregoing formulations and administration methods are intended to be illustrative and not limiting. It will be appreciated that, using the teaching provided herein, other suitable formulations and modes of administration can be readily devised.

16. Combination Therapy

[00463] In one aspect of the disclosed methods, the peptides, nucleic acid molecules, vectors, cells, compositions or pharmaceutical compositions can be administered alone or in combination with one or more additional therapeutic agents. The additional therapeutic agents are selected based on the disease or symptom to be treated. A description of the various classes of suitable pharmacological agents and drugs may be found in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (11th Ed.. McGraw-Hill Publishing Co.) (2005). For example, pharmaceutical compositions containing peptides can be administered in combination with one or more known therapeutic agents for treating atherosclerosis.

[00464] Examples of therapeutic agents that treat vascular disease, cognitive dysfunction and/or neurodegeneration include, but are not limited to, anti-inflammatory agents, antioxidant agents, senolytic agents, lipid lowering agents and liposomes.

[00465] The peptides can be administered in conjunction with or followed by any of the disclosed additional therapeutics.

[00466] The combination therapies can include administering the peptide, nucleic acid molecule, vector, cell, composition or pharmaceutical composition and an additional therapeutic agent during the treatment cycle of a dosing regimen.

EXAMPLES

[00467] It is understood that the disclosed method and compositions are not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[00468] Those skilled in the art w ill recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.

Example 1: Medin is Strongly Associated with AD and VaD

Medin, an aging-associated vascular amyloidogenic protein, is strongly associated with AD and VaD

[00469] Medin, a 50 amino acid protein formed from cleavage of parent protein milk fat globule-EGF factor 8 (MFGE8), is the protein component of the most common human amyloidosis (5, 15). Medin accumulates in the vasculature with aging (5, 15, 20), with aortic medin present in 86% of people over 55 years versus 20% in younger patients (p<0.05)20. As shown herein, medin is present in cerebral arteries of elderly brain donors (7. 8) (FIG. 2) andcerebral arteriole medin (using scoring system from 0 to 3) is higher in AD and VaD versus non-demented donors (ND) (7). Also as shown herein, medin is also highly and independently associated with AD and VaD, and arterial medin content correlated with the burden of classic AD pathologic lesions, (3-amyloid (A(3) plaques and neurofibrillary tangle (NFTs) and VaD lesions (white matter changes) (7). [00470] Medin is also present in coronary arteries, as shown in post-mortem histology of elderly brain and body donors (FIG. 9A-9D). FIG. 9A shows a coronary artery from donor who had myocardial infarction (MI) and diabetes and tissue did not receive anti-medin primary antibody, thus serving as tissue staining control. FIGs. 9B-C show coronary arteries from donors who had MI and diabetes and stained with anti-medin primary' antibody (DAB staining); dark blue/brown stain (appears black on black and white print, sample regions shown with black arrows) denotes medin which is found in tunica intima (endothelial layer), tunica media (smooth muscle layer) as well as tunica adventitia of the coronary⁷ arteries. Medin accumulated in endothelial cells and in smooth muscle layer of coronary artery of a diabetic patient (FIG. 9D).

Medin induces aging-related vascular dysfunction, vascular inflammation and could modulate neuroinflammation

[00471] Preclinical, human ex vivo and in vitro experiments were performed to study how⁷ medin could modulate vascular disease and AD/VaD. C57BL/6J mouse medin has 78% amino acid sequence homology to human medin, with the most aggregation-prone region (near the C terminal) showing high conservation and with propensity for aggregation stronger in human medin versus mouse medin based on TANGO analysis (FIG. 3 A) (21). Aging mice (20 months) showed medin aggregates in brain vasculature (FIGs. 3B-3C) and medin knockout, through targeted deletion of the medin-containing C2 region of MFGE8 (FIG. 3 A. bottom), prevented formation of vascular medin aggregates and aging-associated decline in cerebrovascular function (FIG. 3B, FIG. 3E).

Vascular dysfunction and inflammation induced by medin.

[00472] When exposed to physiologic doses of recombinant medin, ex-vivo human collateral cerebral and peripheral arteries from rapid autopsy brain donors show ed impaired endothelial function (FIG. 4A)(19. 20). This was due to oxidative and nitrative stress: medin reduced arteriole nitric oxide (NO) bioavailability and increased superoxide and peroxynitrite (FIGs. 4B-4D) that was reversed by antioxidant polyethylene glycol superoxide dismutase (PEGSOD) (20). In vitro, 20 hour exposure to medin caused human endothelial cell (EC) pro- inflammatory activation with increased interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1), mediated through nuclear factor-KB (NFKB) activation (FIGs. 4 E-I) (8, 20). To evaluate the role of medin- induced endothelial activation in neuroinflammation, a 3D chip w as created with co-culture of astrocytes (in central chamber) with or without ECs (in side channels) and exposed the cells to medin (FIGs. 4J-4K). Astrocyte IL-8 was higher when astrocytes were co-cultured with ECs, suggesting paracrine coupling with endothelial activation by medin modulating astroglial inflammation (FIG. 4L) (8).

[00473]

Example 2: Medin Immunogen / Vaccine Design

[00474] An immunogen composed of medin epitope was designed to satisfy the following conditionalities: 1) specificity to medin (minimal response against parent MFGE8 so as not to disrupt its native functions or cause unintended injuries to MFGE8 expressing cells). 2) biologic relevance, 3) high immunogenicity (induction of antibody response), and 4) minimized risk of autoimmune response (T cell mediated MHC-I and MHC-II).

[00475] Specificity: To be specific to medin, the epitope from the C-terminal region of medin was chosen whose end will be structurally distinct from parent MFGE8.

[00476] Biologic relevance: The C-terminal portion of medin also happens to be the most aggregation-prone by TANGO analysis prediction (FIG. 3A). that the data herein shows that aggregation-prone oligomeric species of medin have the greatest toxic potential (22).

[00477] High Immunogenicity: The 14 amino acid C terminal portion of medin was chosen for additional studies as the conformation that has high immunogenicity. Indeed, the predicted antigenicity score of the design is 1.24 (OptimumAntigen design tool), signifying high predicted antigenicity.

[00478] Minimize autoimmunity: Autoimmune MHC I and II T cell response was reported to not occur if the native amino acid sequence is shorter than 8 aa in length (24), yet to gain immunogenicity and biologic relevance, the immunogen was expanded to 14 aa length. A construct was prepared substituting 2 aa’s to D-forms instead of native biologically functional L-forms, so that the longest L-aa sequence has 7 aa yet total length is 15 amino acids (including N-terminal cysteine needed to conjugate to KLH). The final vaccine immunogen design was: KLH-C-T’-QGARD-F’-GHIQYVA with T’ and F’ as D-forms. Using NetMHCpan4. 1 software, the design was expected to be a weak binder for the H-2-Dd allele, so T cell-dependent autoimmunity was not expected. Additionally, software predicted that the peptide would remain unstructured irrespective of D- or L-aa presence, thus not expected to alter specificity of developed Abs to the epitope.

[00479] A second construct modified from the aggregation-prone C-terminal region of human medin was prepared, again substituting 2 aa’s to D-forms instead of native biologically functional L-forms, so that the longest L-aa sequence has 7 aa yet total length is 15 amino acids. The second vaccine immunogen design was: KLH- C-T’-QGARN-F - GSVQFVA with T’ and F’ as D-forms. [00480] C57BL/6 and BALB/c mice (N=3 each) were immunized with the medin vaccine KLH-C-T’ -QGARD-F’-GHIQYVA (0.05 mg subcutaneously (SQ) then 0.025 mg 2, 4 and 12 weeks after) and it induced strong antibody responses in both strains (Table 5). C57BL/6 and BALB/c mice (N=3 each) were immunized with second variant medin vaccine KLH- C-T’- QGARN-F’-GSVQFVA and similarly it induced strong antibody responses in both strains (Table 6).

Table 5:

Table 6:

Mouse IgG control

Starting concentration is 40 pg/mL.

Medin Vaccination Produces Antibodies that Conjugate with Human Medin

[00481] Monoclonal antibodies extracted from C57BL/6 mice immunized with KLH-C-T’ - QGARD-F’-GHIQYVA (medin fragment) show ed the ability to attach/conjugate with medin fragment (FIG. 5, lane 5), purified recombinant human medin (FIG. 5, lane 2) and medin polypeptides in human umbilical vein endothelial cells (FIG. 5, lane 3). This shows that the medin vaccination approach produced antibodies that conjugate with human medin.

[00482] Monoclonal antibodies extracted from C57BL/6 mice immunized with KLH-C-T - QGARD-F’-GHIQYVA were mixed with medin (5 uM) and showed reduction of inflammatory' response in human brain microvascular endothelial cells (ICAM-1 Gene Expression, FIG. 6A and VCAM-1 Gene Expression, FIG. 6B) in vitro after 20 hours of exposure when compared to medin alone. Thus, this vaccination approach is effective at producing an immune response that reverses medin cellular toxicity⁷.

[00483] Following immunization of rabbits with human medin, polyclonal antibodies targeting 3 epitopes of medin were created (FIG. 10A). When human endothelial cells were treated with medin, there was increased pro-inflammatory gene expression (IL-8. IL-6 and IL-1 (3), and the pro-inflammatory effect of medin was reduced when medin was co-treated with polyclonal antibodies derived from medin vaccination of rabbits. (FIG. 10B).

Example 3: Evaluate Optimal Anti-Medin Vaccination Regimen

[00484] The optimal anti-medin vaccination regimen will be tested on two animal models: 1) C57BL/6 mice and 2) SAMP8 mice.

[00485] Rationale: C57B/6 mice do not show medin amyloid in cerebral arteries at 2-3 months but levels increased with aging to 20 months, associated with cerebrovascular dysfunction (FIG. 3) (21). SAMP8 is a well-established model of aging (including cognitive and vascular dysfunction) (38-41) and polygenic late onset AD (46). The data shows that cerebral arterial medin was 2.9±0. 1 A. U. in 12 month versus 0.3±0.2 AU in 2 month old SAMP8 mice (pO.OOl, using semiquantitative scoring system (7) from 0-3) (FIG. 7), supporting the potential role of vascular medin in SAMP8 neuropathology⁷.

Medin vaccine dosing optimization

[00486] The medin immunogen designed/tested (KLH-C-T’-QGARD-F’-GHIQYVA) was chosen for additional experiments. Optimum medin vaccine administration to maintain antibody response will be tested (47). Two dosing regimens will be compared: A: 0.05 mg (Time 0). 0.025 mg (Time 2 weeks, 4 weeks, 12 weeks) SQ (similar to regimen used in Table 1), or higher dose regimen B: 0. 1 mg (Time 0), 0.05 mg (Time 2 weeks, 4 weeks, 12 weeks) SQ. Medin-KLH will be in 100 pL aqueous solution given with 100 pL Freund’s adjuvant. Vaccination will be in 12-month old C57BL/6 and 3-month old SAMP8 mice (N=4 mice, ! male, !4 female) and anti-medin immunogen antibody production will be measured at 4 weeks after last injection using indirect ELISA of mouse sera. The superior regimen will be chosen for the efficacy studies. Test efficacy of anti-medin vaccination

[00487] Medin vaccine or vehicle control will be injected into 12-month-old C57BL/6 and 3- month-old SAMP8 mice using optimal regimen from 1 A (N=20 per treatment arm, Vz male,/z female) (FIG. 8). The outcomes will be measured in 20-month-old C57BL/6 and 12- month-old SAMP8 mice (age known to show medin amyloid accumulation). Primary outcome measures will be 1) cerebrovascular and brain parenchymal medin content, 2) cognitive function. 3) cerebrovascular function, 4) cerebrovascular and brain parenchymal inflammation. Secondary outcome measures will include serum anti-medin antibody level, neuropathology and aortic medin. Outcome measures will be measured using the following: vascular and brain medin will be quantified using immunofluorescence (IF) or immunohistochemistry (IHC) using anti-medin antibody, cognitive function will be measured using novel object recognition (NOR) testing, cerebrovascular function will be measured using ex-vivo middle cerebral artery endothelial and smooth muscle dependent function, inflammation and neurovascular pathology⁷ will be assessed using IF/IHC as described (7, 8, 19, 20).

[00488] Cognitive function: Discrimination ratios of 3 variations of NOR tasks adapted from our prior work will be measured (48, 49) to evaluate short-term, long-term and working memory⁷. These are the tasks to evaluate because of the 4-day time frame for evaluation without substantial training. The NOR, novel object location (NOL) and temporal order object recognition (TOR) assess short-term, long-term and working memory, respectively (50, 51).

[00489] Cerebrovascular function will be assessed (52, 53). Middle cerebral arteries will be cannulated and myogenic response (vessel diameter) to 0/30/60/90-mm Hg pressure (30 minutes stabilization for each) measured. The vessel will then be preconstricted with increasing doses of endothelin-1 until it reaches -60% max diameter. Baseline vasoreactivity will be assessed using acetylcholine (10-9-10-4M) to assess endothelium-dependent vasodilation and NO donor (Z)-l-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-l- ium-l,2-diolate (DETA-NONOate) (10-4M) to assess smooth muscle-dependent vasodilation.

[00490] Cerebrovascular and coronary medin and neurovascular pathology: Cerebrovascular and coronary medin will be assessed using IHC/IF using anti-mouse medin antibodies (custom-made for us by Genscript) in the circle of Willis and leptomeningeal arteries and in hippocampal parenchymal arterioles. Quantification of % vessel area will be done using Image J. Vascular inflammation will be assessed in the same arteries using IHC/IF using antibodies against phosphorylated NFKB, IL-8, IL-6, ICAM-1 and VCAM-1.

[00491] Neurodegeneration will be assessed using synaptophysin IHC/IF to measure synaptic content, since synaptic loss which can represent neuronal loss as well as synaptic degeneration, is a maj or pathologic abnormality' in AD and correlates with degree of cognitive dysfunction (54, 55). Neuroinflammation will be assessed using IHC/IF of activated astrocytes (glial fibrillary acidic protein GFAP) (8) and microglia (ionized calcium- binding adaptor molecule 1, Ibal).

[00492] Sample size calculation, Data Analyses, Sex as a Biologic Variable: Based on FIG. 3C results N=20 mice per group (C57BL/6 or SAMP8) will be used to show a mean difference of 0.185 ng/mg vascular medin (standard deviation 0.27 and 0.05 with 80% power, a=0.05). Outcome measures will be compared using unpaired Student’s t-test (data with normal distribution) or Mann-Whitney test (data not normally distributed). Correlation analyses between cerebrovascular medin and other outcome measures using Pearson (parametric) or Spearman (non-parametric) analyses will be performed. Per Guidelines for Rigor and Reproducibility, the data will be disaggregated and analyzed by sex.

[00493] It is expected that mice receiving medin vaccine will develop anti-medin antibodies that will interact with newly produced medin, prevent it from aggregating into oligomers/fibrils and be cleared by the immune system. Vaccinated mice will show less cerebrovascular medin and improved cognitive/cerebrovascular function versus controls. It is expected that that cerebrovascular medin burden is inversely correlated with cognitive/cerebrovascular function, and directly⁷ correlated with vascular inflammation and neurovascular pathology. The vaccine was designed to be immunogenic to medin and spare parent protein MFGE8 so as not to disrupt MFGE8 physiologic functions (e.g., apoptosis signaling (56)). This will be confirmed by measuring tissue MFGE8. In case MFGE8 is also reduced/impaired by vaccination, beneficial effects are expected as it was recently reported that aging-associated MFGE8 accumulation causes proin fl ammatoiy vascular remodeling which is prevented by MFGE8 knockout (57).

[00494] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

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Claims

CLAIMS We claim:

1. A peptide comprising: a) a carrier epitope, b) a cysteine residue, and c) a modified medin peptide, wherein the modified medin peptide comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2, or a fragment thereof, wherein the modified medin peptide or fragment thereof comprises at least one amino acid in the D-form and no more than 8 consecutive amino acids are in the L-form.

2. The peptide of claim 1, wherein the carrier epitope is at the N terminus of the peptide.

3. The peptide of claim 2. wherein the modified medin peptide is at the C-terminus of the peptide.

4. The peptide of any of claims 1-3, wherein the modified medin peptide or fragment thereof is 12-18 amino acids long.

5. The peptide of any of claims 1-4, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TQGARDFGHIQYVA (SEQ ID NO: 4) or TQGARNFGSVQFVA (SEQ ID NO: 3).

6. The peptide of claim 5, wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 3 are in the D-form or wherein amino acids T at position 1 and F at position 7 of SEQ ID NO: 4 are in the D-form.

7. The peptide any of claims 1-4, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGSSKEVTGIITQGARNFGSVQFVA (SEQ ID NO: 5) or LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

8. The peptide of any of claims 1-4, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARNFGSVQFVA (SEQ ID NO: 7) or TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

9. The peptide any of claims 1-4, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of LGTQRQVTGIITQGARDFGHIQYVA (SEQ ID NO: 6).

10. The peptide of any of claims 1-4, wherein the modified medin peptide or fragment thereof comprises or consists of the amino acid sequence of TGIITQGARDFGHIQYVA (SEQ ID NO: 8).

11. The peptide of any one of claims 1-10, wherein the carrier epitope is a KLH protein.

12. A nucleic acid molecule capable of encoding any of the peptides of any one of claims 1-11.

13. A vector comprising a nucleic acid molecule of claim 12.

14. A cell comprising a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, or a vector of claim 13.

15. A composition comprising a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, or a cell of claim 14.

16. A pharmaceutical composition, comprising a peptide of any one of claims 1- 11, a nucleic acid molecule of claim 12, a vector of claims 13, a cell of claim 14, or a composition of claim 15, and a pharmaceutically acceptable carrier.

17. A method of disrupting medin toxicity in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

18. A method of reversing medin induced endothelial activation in a subj ect in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15. or a pharmaceutical composition of claim 16.

19. A method of inducing an immune response in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12. a vector of claim 13. a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 1 .

20. A method of vaccinating a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

21. A method of attenuating medin-induced vascular dysfunction or neurovascular pathology in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11. a nucleic acid molecule of claim 12. a vector of claim 13. a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

22. A method of modulating vascular disease in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 1 .

23. A method of modulating medin aggregation in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

24. A method of treating or preventing vascular dysfunction or inflammation induced by medin in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

25. A method of reducing interleukin (IL)-8, IL-6, intercellular adhesion molecule-1 (ICAM-1) or plasminogen activator inhibitor-1 (PAI-1) in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

26. A method of modulating or preventing cerebrovascular dysfunction, cognitive dysfunction, neurodegeneration and/or neurovascular pathology in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12. a vector of claim 13. a cell of claim 14, a composition of claim 15. or a pharmaceutical composition of claim 16.

27. A method of modulating or preventing amyloid plaque formation in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

28. A method of reducing the rate of growth of amyloid plaques in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-1 1, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

29. A method of treating coronary artery disease and/or ischemic heart disease in a subject in need thereof comprising administering an effective amount of a peptide of any one of claims 1-11, a nucleic acid molecule of claim 12, a vector of claim 13, a cell of claim 14, a composition of claim 15, or a pharmaceutical composition of claim 16.

30. The method of any of claims 17-28, wherein the effective amount of the peptide of any one of claims 1-11, the nucleic acid molecule of claim 12, the vector of claim 13, the cell of claim 14, the composition of claim 15, or the pharmaceutical composition of claim 16 generates an immune response in said subject.

31. The method of claim 30, wherein the immune response is specific to the peptide of any one of claims 1-11, the nucleic acid molecule of claim 12, the vector of claim 13, the cell of claim 14, the composition of claim 15, or the pharmaceutical composition of claim 16.

32. The method of claim 30 or claim 31, wherein the immune response does not generate an immune response or generates a minimal immune response to MFGE8.