MX2008004255A - Novel peptides for treating and preventing immune-related disorders, including treating and preventing infection by modulating innate immunity - Google Patents

Abstract

In one aspect, the present invention provides isolated novel peptides that can be used to modulate innate immunity in a subject. and/or for the treatment of an immune-related disorder, including treating and preventing infection by modulating innate immunity. Also provided are an agent reactive with the peptide, a pharmaceutical composition that includes the peptide, an isolated nucleic acid molecule encoding the peptide, a recombinant nucleic acid construct that includes the nucleic acid molecule, at least one host cell comprising the recombinant nucleic acid construct, and a method of producing the peptide using the host cell. The present invention further provides a method for treating and/or preventing infection in a subject by administering the peptide of the invention to the subject, thereby modulating innate immunity in the subject. Additionally, the present invention provides a method for predicting whether a subject would be responsive to treatment with a peptide of the invention.

Description

NEW PEPTIDES TO TREAT AND PREVENT DISORDERS RELATED TO THE IMMUNE SYSTEM, INCLUDING THE TREATMENT AND PREVENTION OF INFECTION BY IMMUNITY MODULATION INNATA FIELD OF THE INVENTION This invention relates to peptides for use in the treatment and prevention of disorders related to the immune system including the treatment and prevention of infection by modulation of innate immunity. In one aspect, the composition refers to the compositions and uses thereof for modulating innate immunity. In still another aspect, the invention provides the novel peptides and uses thereof, effective to reduce the activity of DPPIV.

BACKGROUND OF THE INVENTION A variety of microorganisms, including viruses, bacteria, fungi and parasites can cause diseases.

Microbial cells are distinct from the cells of animals and plants - which are incapable of living alone in nature, existing only as parts of multicellular organisms. Microbial cells can be pathogenic or non-pathogenic, depending, in part, on the microorganism and host status. For example, in a host REF. : 191420 immunocompromised, a normally harmless bacterium can become a pathogen. The entry into the host cells is critical for the survival of bacterial pathogens that replicate in an intracellular medium. For organisms that replicate in extracellular sites, the significance of bacterial entry to host cells is less well defined. Drug resistance remains an obstacle in the continuous effort to fight infections. For example, penicillin was effective in treating Staphylococcus aureus, until the bacteria became resistant. Throughout the second half of the 20th century, new antibiotics were developed, such as vancomycin and methicillin; These successfully cured S. aureus infections. However, strains resistant to methicillin from S. aureus evolved in the 1970s, and have been plaguing hospitals worldwide since then. More recently, strains of S. aureus resistant to vancomycin have emerged. With the increasing threat of resistance to antimicrobial drugs and the emergence of new infectious diseases, there continues to be a continuing need for therapeutic compounds. The therapeutic agents that act on the host, not the pathogen, are desirable, because they do not promote resistance pathogenic In particular, drugs that act on the host, via the innate immune system, provide a promising source of therapeutic agents. The host's defense against microorganisms begins with the epithelial barriers of the body and the innate immune system, and culminates with the induction of the adaptive immune response. The host's innate immune response encompasses a group of highly conserved mechanisms that recognize and attack microbial infections. The elements of innate immunity are continuously maintained at low levels, and are activated very quickly, when stimulated. The innate immune response begins with events that occur immediately after exposure to a microbial pathogen. Events associated with adaptive immunity, such as rearrangement of the immunoglobulin receptor genes, are not considered part of the innate response. There is evidence that indicates that innate responses are instrumental in controlling most infections, and also contribute to inflammatory responses. The inflammatory responses triggered by the infection are known to be central components of the pathogenesis of the disease. The importance of Toll-like receptors (fee) (TLRs) in the innate immune response has also been well characterized. The mammalian family of TLRs recognizes conserved molecules, many of which are found on the surfaces of, or are released by, the microbial pathogens. There are numerous other mechanisms, less well characterized, that initiate and / or contribute to the innate defense of the host. The innate immune system provides a range of protective mechanisms, including the function of the epithelial barrier and the secretion of cytokines and chemokines. To date, four chemokine families have been categorized, according to the number of conserved N-terminal cysteine portions: C, CC, CXC, and CX3C, where X is a non-conserved amino acid residue. It is known that CXC chemokines are chemotactic for cells that possess the CXCR3 receptor, including monocytes, activated T cells (Thl), and NK cells. The primary human epithelial cells of the respiratory tract, and the 16-HBE cell line, constitutively express the receptor of CXCR3 and its ligands, IP-10, I-TAC, and MIG (Kelsen et al, The chemokine receptor CXCR3 and its splice variant are expressed in human air and epithelial cells, Am. J. Physiol, Lung Cell Mol. Physiol., 287: L584, 2004). In addition, the ligands of CXCR3 induce chemotactic responses and the reorganization of actin in 16-HBE cells (Kelsen et al., The chemokine receptor CXCR3 and its splice variant are expressed in human airway epithelial cells, Am. J. Physiol. Lung Cell Mol. Physiol., 287: L584, 2004). In addition, serine proteases, transmebranal dipeptidyl-peptidase IV (DPPIV), type II, also known as CD26 or adenosine deaminase binding protein, is a major regulator of various physiological processes that include immune functions. CD26 / DPPIV is a 110-kD cell surface glycoprotein that is mainly expressed on mature thymocytes, activated T cells, B cells, NK cells, macrophages, and epithelial cells. It has at least two functions, a function of signal transduction and a proteolytic function (Morimoto C, Schlossman SF, The structure and function of CD26 in the T-cell immune response, Immunol., Review, 1998, 161: 55-70. ). One of its cellular roles involves the modulation of chemokine activity by cleaving the dipeptides from the N-terminus of chemokine. The modulation of the NH2 ends of the chemokines is of great importance not only for binding to their receptors and the following reactions, but also for altering the specificity of the chemokine receptor processed. The activity of DPPIV has been associated with a number of conditions related to the immune system.

BRIEF DESCRIPTION OF THE INVENTION The inventors have discovered that the peptides that have the amino acid sequence of one of the peptides listed and described in Table 1 or an analogue, derivative or variant thereof, can improve an innate immunity of the host. In one aspect, it was found that the immunomodulatory peptides of the invention lack antimicrobial activity, while demonstrating an ability to improve survival in infected hosts. In still another aspect, the invention provides peptides that modulate DPPIV activity. In one aspect, the invention provides peptides that reduce the activity of DPPIV. In still another aspect, the invention provides peptides that can be used in the diagnosis, treatment or prevention of an immune disorder, such as one associated with DPPIV activity and / or innate immunity. Accordingly, in one aspect, the present invention provides an isolated peptide that includes the amino acid sequence of any of Table 1 or a derivative analogue or variant thereof, or the obvious chemical equivalent thereof, or a peptide comprising said peptide . In one embodiment, the peptide is up to 10 amino acids comprising the peptide. By way of example, the isolated peptide may have a modified C-terminus (eg, an amidated C-terminus) and / or a modified N-terminus. The isolated peptide of the invention may further include the amino acid sequence of Table 1 as modified by at least one substitution of a D-amino acid. The isolated peptide may further include a modified backbone or backbone, by way of example, wherein the N-terminus is modified from an amide to an N-methyl. In one aspect, those modified peptides that retain the immunological activity of the parent peptide and the obvious chemical equivalent thereof, which retain such activity, are encompassed within the scope of the present invention. In still another aspect, the present invention further provides an agent reactive with an isolated peptide, which includes the amino acid sequence of Table 1, or an analog, derivative or variant thereof. In one embodiment, the agent is an antibody of non-natural origin (e.g., a polyclonal or monoclonal antibody). In one embodiment, the antibody is made using a MAPS antigen linked to the peptide of the present invention via 2 glycine residues inserted at the C-terminus of the peptide. The construct can then be administered to an animal, such as a rabbit, and the antibody harvested using methods well known in the art. In one aspect, such agents can be used or labeled to label peptides of the invention. In yet another aspect, such agents can be used in diagnostic and screening methods to monitor agents that can modulate activity peptide or to quantify the amount of the peptide. In yet another aspect, the present invention provides an isolated nucleic acid molecule encoding an isolated peptide having or comprising the amino acid sequence of Table 1 or an analog, derivative or variant thereof. A recombinant nucleic acid construct is also provided which includes the nucleic acid molecule operably linked to an expression vector. In additional aspect, the present invention provides at least one host cell comprising the recombinant nucleic acid construct of the invention. A method is also provided for producing a peptide having or comprising the amino acid sequence of Table 1 or an analog, derivative or variant thereof, by: (a) cultivating at least one host cell, under conditions that they allow the expression of the peptide; and (b) recovering the peptide from at least one host cell or culture medium thereof. In yet another aspect, the present invention provides a pharmaceutical composition that includes an isolated peptide having or comprising the amino acid sequence of Table 1 or an analog, derivative or variant thereof (including a pharmaceutically acceptable salt, salt by addition or ester of any of the above or polymorph), in combination of a pharmaceutically acceptable carrier, diluent or excipient. In still another aspect, the present invention provides a method for treating and / or preventing infection (e.g., a microbial infection) in a subject by administering to a subject a peptide having or comprising an amino acid sequence of Table 1 or an analog or derivative or variant thereof, or the obvious chemical equivalent thereof. As an example, the subject may have or be at risk of having the infection. In one embodiment, the peptide modulates the innate immunity of the subject, thereby treating and / or preventing infection in the subject. The present invention further provides a method for identifying a bacterial infection that can be treated with a peptide of the invention. In yet another aspect, the invention provides a method for treating or preventing a condition or disorder related to DPPIV. Exemplary infections that can be treated and / or prevented by the method of the present invention include an infection by a bacterium (eg, a gram positive or a gram negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp. , Staphylococcus aureus, Streptococcus spp. , or vancomycin-resistant enterococci). In yet another embodiment, the infection is a fungal infection (for example, infection by a mold, a yeast or a higher fungus). In another embodiment, the infection is a parasitic infection (for example, infection by a unicellular parasite). or multicellular, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondii). In yet another embodiment, the infection is a viral infection (eg, infection by a virus associated with AIDS, bird flu, chicken pox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and upper and lower respiratory tract infection (for example, respiratory syncytial virus)). According to the method of the present invention, a peptide having or comprising the amino acid sequence of Table 1, or an analog, derivative or variant thereof, can be administered to the subject directly (eg, by administration of the peptide same) or indirectly (eg, by administering to the subject a nucleic acid sequence encoding the peptide, in a manner that allows expression of the peptide in the subject) The peptide of the invention (or the nucleic acid encoding the can be administered orally to the subject, parenterally (eg, intradermally, intramuscularly, intraperitoneally, intravenously, or subcutaneously), transdermally, intransally, by pulmonary administration (e.g., by intratracheal administration), and / or by osmotic pump. In still another aspect, the present invention provides a method for predicting whether or not a subject could respond to treatment with a peptide comprising the amino acid sequence of Table 1, or an analog, derivative or variant thereof, by evaluating a diagnostic sample of the subject for DPPIV activity, wherein the modulation, such as the reduction of DPPIV activity is indicative that the subject could respond to treatment by the peptide. In one aspect, the subject has or is suspected of having the DPPIV-related condition or disorder. Additional aspects and advantages of the present invention will be apparent in view of the following description. It should be understood however that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are all by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES The invention will now be described in relation to the figures, in which: Figures 1A and IB describe the results of the experiment described in example 2.% viability = the amount of bacterial growth in relation to the control with vehicle (Tris), which is established at 100% bacterial survival with the respective peptides SEQ. ID. Nos. 5, and 47; Erythr. = erythromycin Figures 2A-2G describe the results of the experiment described in Example 3. The graph shows the colony forming units per mi (CFU / ml) on the Y axis, and the treatment group (control = no peptide; SEQ. Nos. 1, 4, 5, 6, 45 and 47 = treatment with a peptide having the respective amino acid sequence) on the X axis. The bacterial count of the individual mice is shown. Figures 3A and 3B describe the results of the experiment described in Example 4. The graph shows the colony forming units per my (CFU / ml) on the Y axis, and the treatment group (control = no peptide; SEQ. Nos. 1 and 5 = treatment with a peptide having the respective amino acid sequence) on the X axis. The bacterial count of the individual mice is shown.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Related DPPIV disorder" or "DPPIV-related condition" or "condition associated with DPPIV" as used herein, means any medical condition that has been correlated with the activity of DPPIV and wherein the modulation of said activity may be used to treat and / or prevent or diagnose the condition. Examples of such conditions include, but are not limited to: HIV / AIDS, autoimmune conditions, such as rheumatoid arthritis, multiple sclerosis, cancer (e.g., colon and lung), diabetes and Graves' disease. "Immune system related disorder" is a condition that is associated with the immune system of a subject, either through the activation or inhibition of the immune system, which can be treated, prevented or diagnosed by addressing a certain component of the immune system. immune response to a subject, such as the innate immune response. "Immunologically active" as used herein, refers to the innate immune activity (eg, the ability to modulate the innate immune response or the component thereof in a subject) or the ability to Modulate the activity of DPPIV. "Modular" or "modulation" as used herein, for example, such as modulation of the activation of DPPIV activity or a particular response, covers the increase or decrease of the activity or response in relation to a control or the normal or baseline level of the activity, or the response under certain conditions. This may also encompass the maintenance of a level of activity or response under conditions that would normally increase or decrease the level of activity of the peptide or response. "Pharmaceutically acceptable salts" refer to the non-toxic alkali metal, alkaline earth metal, and ammonium salts commonly used in the pharmaceutical industry, including the sodium, potassium, lithium, calcium, magnesium, barium, ammonium salts and zinc protamine, which are prepared by methods well known in the art. The term also includes the non-toxic acid addition salts, which are generally prepared by the reaction of the compounds of this invention with a suitable organic or inorganic acid. Representative salts include the salts of hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, trifluoroacetate and the like .

"Salt by pharmaceutically acceptable addition" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, melic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. For a description of the pharmaceutically acceptable acid addition salts as prodrugs, see Bundgaard, H., ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam. "Pharmaceutically acceptable ester" refers to those esters which retain, after hydrolysis of the ester linkage, the biological effectiveness and properties of the carboxylic acid or alcohol, and are not biologically or otherwise undesirable. For a description of pharmaceutically acceptable esters as prodrugs, see Bundgaard, H., supra. These esters are typically formed from the corresponding carboxylic acid and an alcohol. In In general, ester formation can be achieved via conventional synthetic techniques. (See, for example, March, Advanced Organic Chemistry, 3rd Ed., John Wiley &Sons, New York (1985) pp. 1157 and references cited therein, and Mark et al., Encyclopedia of Chemical Technology, John Wiley &Sons, New York (1980).) The alcohol component of the ester will generally comprise (i) an aliphatic alcohol of 2 to 12 carbon atoms which may or may not contain one or more double bonds and may not contain branched carbon chains or (ii) aromatic or heteroaromatic alcohols of 7 to 12 carbon atoms. This invention also contemplates the use of those compositions which are esters as described herein, and at the same time are pharmaceutically acceptable acid addition salts, thereof. "Pharmaceutically acceptable amide" refers to those amides which retain, after hydrolysis of the amide bond, the biological effectiveness and properties of the carboxylic acid or the amine, and are not biologically or otherwise undesirable. For a description of the pharmaceutically acceptable amides as prodrugs, see Bundgaard, H., ed., Supra. These amides are typically formed from the corresponding carboxylic acid and an amine. In general, the formation of the amide can be achieved by means of conventional synthetic techniques. (See, for example, March, Advanced Organic Chemistry, 3rd Ed., John Wiley &Sons, New York (1985) p. 1152 and Mark et al., Encyclopedia of Chemical Technology, John iley & Sons, New York (1980).) This invention also contemplates the use of those compositions which are amides as described herein, and at the same time are pharmaceutically acceptable acid addition salts, thereof. "Pharmaceutically or therapeutically acceptable carrier" refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredients and that is not toxic to the host or to the patient. "Stereoisomer" refers to a chemical compound that has the same molecular weight, the same chemical composition, and constitution as another, but with atoms grouped differently. That is, certain identical chemical portions are in different orientations in space and, therefore, when they are pure, they have the ability to rotate the plane of polarized light. However, some pure stereoisomers may have an optical rotation that is so slight that it is undetectable with current instrumentation. The compounds of the present invention can have one or more asymmetric carbon atoms, and therefore, include various stereoisomers. All immunologically active stereoisomers are included within the scope of the invention.

"Therapeutically or pharmaceutically effective amount" as applied to the compositions of the present invention refers to the amount of the composition, sufficient to induce a desired biological result. This result can be the relief of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. For example, in the present invention, the result will typically involve the improvement of the innate immune response, the reduction of DPPIV activity and / or the modulation thereof (such as inhibition or reduction or non-stimulation) of inflammatory responses. for infection or tissue damage. The amino acid residues in the peptides are abbreviated as follows: phenylalanine is Phe or F; leucine is Leu or L; isoleucine is lie or I; methionine is Met or M; valina is Val or V; Serine is Ser or S; proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; tyrosine is Tyr or Y; histidine is His or H; Glutamine is Gln or Q; Asparagine is Asn or N; Lysine is Lys or K; Aspartic acid is Asp or D; Glutamic acid is Glu or E; Cysteine is Cys or C; Tryptophan is Trp or W; arginine is Arg or R; and glycine is Gly or G. In addition, the abbreviation Nal is used to denote 1-naphthylalanine; ornithine is Orn or O, Cit is citrulline, Hci is citrulline with one or more methylene groups, and Vx or valine x, where "x" refers to a variation in the amino acid backbone, wherein the amino acid bond is no longer an amide bond, but a methylated amine, which applies similarly to other amino acids with the designation "x". Also, 2,4-diaminobutyric acid is Dab; 2,3-diaminopropionic acid is Dpr or Dapa; the N- (4-aminobutyl) -glycine is Nlys; hSer is homoserine; Hyp is hydroxyproline; Val (betaOH) is hydroxy valine; D-Pro is 3, dehydroproline; Pyr is pyroglutamine (proline with C = 0 in the ring); the proline with fluorine substitutions on the ring; 1,3-thiazolidin-4-carboxylic acid (proline with S in the ring); Thi is beta- (2-thienyl) -alanine; Abu is 2-aminobutyl acid; Nva is norvaline; Nle is norleucine; Hol is homoleucine; and Aib is alpha-aminoisobutyric acid. In addition to peptides consisting solely of naturally occurring amino acids, peptide mimics or peptide analogs are also provided. Peptide analogues are commonly used in the pharmaceutical industry as non-peptidic drugs with properties analogous to those of the template peptide. These types of non-peptide compounds are termed "peptide mimetics" or "peptidomimetics" (Fauchere, J., Adv. Drug Res 15: 29 (1986); Veber and Freidinger, TINS p.392 (1985); and Evans et al. , J Med. Chem. 30: 1229 (1987), which are incorporated by reference herein). Peptide mimetics that are structurally cellular to peptides Therapeutically useful can be used to produce an equivalent or improved therapeutic or prophylactic effect. In general, peptidomimetics are structurally similar to a paradigm peptide (e.g., a peptide having a biological or pharmacological activity), such as a peptide of natural origin that binds to the receptor, but have one or more optionally replaced peptide bonds by a bond selected from the group consisting of: -CH2NH-, -CH2-S-, -CH2 = CH2-, -CH = CH- (cis and trans), -C0CH2-, -CH (0H) CH2-, and . -CH2S0-, by methods known in the art and further described in the following references: Spatola, A. F. in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds. , Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Vega Data (March 1983), Vol. 1, Issue 3, PEPTIDE BACKBONE MODIFICATIONS (general review); Morley, Trends Pharm Sci (1980) pp. 463 468 (general review); Hudson, D. et al., Int J Pept Prot Res 14: 177-185 (1979): (- CH2NH-, CH2CH2-); Spatola et al., Life Sci 38: 1243-1249 (1986): (-CH2-S); Hann J. Chem. Soc. Perkin Trans. I 307 314 (1982): (-CH-CH-, cis and trans); Almquist et al., J Med Chem 23: 1392-1398 (1980): (-COCH2-); Jennings-White et al., Tetrahedron Lett 23: 2533 (1982): (- COCH2-); Szelke et al., European Application. EP 45665 CA: 97: 39405 (1982) (-CH (OH) CH2.); Holladay et al., Tetrahedron Lett 24: 4401 4404 (1983): (-C (OH) CH2-); and Hruby Life Sci 31: 189-199 (1982): (-CH2-S-); each of which is incorporated by reference herein. In one aspect, the non-peptide bond is -CH2NH--. Such peptidic mimetics may have significant advantages over the modalities of the polypeptides including, for example: more economical production, greater chemical stability, improved pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g. a broad spectrum of biological activities), reduced antigenicity and others. Labeling of the idomimetic peptides usually involves the covalent linking of one or more markers, directly or through a spacer (eg, an amide group), to the position (s) that do not interfere with the peptidomimetic, which are predicted by the data. quantitative structure-activity and / or molecular modeling. Such non-interference positions are in general positions that do not form direct contacts with the macromolecule (s) (eg, molecules of the immunoglobulin superfamily) to which the peptidomimetic bonds produce the therapeutic effect. Derivatization (eg, labeling) of the peptidomimetics should not substantially interfere with the desired biological or pharmacological activity of the peptidomimetic. In general, the peptidomimetics of the receptor binding peptides bind to the receptor with high affinity, and possess detectable biological activity (eg, they are agonists or antagonists for one or more phenotypic changes mediated by the receptor). The systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (for example, D-lysine instead of L-lysine) can be used to generate more stable peptides. It is appreciated that those D-amino acid substitutions wherein the immunological activity of the peptide is conserved are desired. As described herein, the inventors have identified novel peptides having and / or comprising the amino acid sequences as shown in Table 1 or an analog, derivative or variant of the amino acid sequence described herein. The inventors have also shown that a peptide having or comprising one of the amino acid sequences of Table 1, and an amidated C-terminus, has therapeutic utility in the improvement of innate immunity. In particular, the inventors have shown that a peptide comprising an amino acid sequence of Table 1, lacked antimicrobial efficacy against S. aureus, and still provided in vivo protection infected with S. aureus. The peptide improved host response to infection, resulting in improved bacterial clearance and host survival. In this way, the new The disclosed peptides can be used as a therapeutic agent for the treatment of infectious disease. In yet another embodiment, the peptides of the invention have been shown to reduce the activity of DPPIV, which has been shown to be related to a number of disorders related to the immune system, such as AIDS and the progression of the disease by HIV (Blazquez et al., 1992; Vanham et al., 1993; Schols et al., 1998 Oravecz et al., 1995), Graves disease (Eguchi et al., 1989; Nishikawa et al., 1995), and cancer (Stecca et al., 1997), such as lung or colon cancer, and diabetes (Hinke et al., 2000; Marguet et al., 2000). In addition, DPPIV as an indicator of T cell activation has been shown to fluctuate in parallel with several autoimmune diseases such as rheumatoid arthritis (Nakao et al., 1989) and autoimmune thyroiditis (Eguchi et al., 1989). DPPIV has been described as a marker that correlates well with the level of activity of these diseases. This has also been studied as an indicator of the progression of the disease in chronic progressive multiple sclerosis (Constantinescu et al., 1995). The peptides of the invention can be used in the treatment of such conditions.

Peptides of the Invention Accordingly, the present invention provides isolated peptides having or comprising the amino acid sequence of Table 1 or an immunologically active analog, derivative or variant thereof. Also provided are pharmaceutically acceptable salts, acid addition salts and esters of the peptides, analogs, derivatives and variants of the invention, including those described herein, such as conservative substitution, and modifications at the N-terminus. and C, and modifications to the main chain or backbone, as described herein. As used herein, an "isolated" peptide of the invention, is a peptide that has no counterpart of natural origin or that has not been separated or purified from the components that naturally accompany it. An isolated peptide of the invention can be obtained, for example, by the expression of a recombinant nucleic acid encoding the peptide, or by chemical synthesis. Because a peptide that is chemically synthesized is, by its nature, separated from the components that naturally accompany it, the synthetic peptide is "isolated." In one aspect, the isolated peptide of the invention comprises the amino acid sequence having the formula: "XiX2P" (SEQ ID No. 55), wherein: Xi is selected from the group consisting of K, H, R, S, T, O, Cit, Hci, Dab, Dpr, or glycine-based compounds with basic functional groups substituted on the N-terminus (eg, Nlys), hSer, Val (betaOH), or in another embodiment, is selected from a group consisting of K, R, S, 0, and Cit, or in another, more it is selected from the group consisting of K, R, and S, or is R; and wherein X2 is selected from the group consisting of V, I, K, P, and H. In one embodiment, the isolated peptide of the invention is SEQ. ID. No. 55. In still another aspect, this is a peptide of up to 10 amino acids comprising an amino acid sequence of SEQ. ID. No. 55. In one embodiment, the peptide isolated from SEQ. ID. No. 55 is the SEQ. ID. Nos. 8, 9, 26, 39, 40, 41, and 45-53, or an isolated peptide of up to 10 amino acids comprising said sequences. In still another embodiment, the isolated peptide comprising SEQ. ID. No. 55 is the SEQ. ID. No.44, which is up to 13 amino acids. In yet another embodiment, the invention provides an isolated peptide comprising the formula: "X1X2X3P" (SEQ ID No. 56) wherein Xi is selected from the group consisting of K, H, R, S, T, O, Cit, Hci, Dab, Dpr, or glycine-based compounds with basic functional groups substituted on the N-terminus (e.g., Nlys), hSer, Val (betaOH), or in any other embodiment, is selected from the group consisting of K , H, R, S, T, and O, or in another modality, K, H, R, S, and T, or in another modality, K, H, R, S and O, or in another modality more , R, H, K and S; and where X2 is selected from the group that consists of A, I, L, V, K, P, G, H, R, S, 0, Dab, Dpr, Cit, Hci, Abu, Nva, Nle and where X2 may be N-methylated, or in another modality, selected from the group consisting of A, I, L, V, K, P, G, H, and R, wherein this may be N-methylated; and wherein X3 is selected from the group consisting of I, V, P, wherein in one embodiment, X3 is not N-methylated. In one embodiment the isolated peptide can be an amino acid sequence of up to 10 amino acids, comprising SEQ. ID. No. 56, which includes SEQ. ID. Nos. 1, 3-7, 10-16, 18, 21-25, 27, 28, 31-39, 42, 43, or 47, or an isolated peptide of up to 11 amino acids comprising SEQ. ID. No. 54. However, in one modality, when SEQ. ID. No. 56 is a hexamer, this is not the SEQ. ID. No. 2, or when in a modality, when this is a pentamer, this is not SEQ. ID. No. 17. In one embodiment, the isolated peptide of the invention does not comprise a peptide that includes SEQ. ID. Nos. 2 or 17. In still another embodiment, the invention provides an isolated peptide comprising the peptide including the formula of SEQ. ID. No. 56 in a pentamer or hexamer. In one embodiment, the peptide is immunologically active. In one embodiment, the isolated peptide of the invention comprises a peptide of the formula "aXiX2X3P" (SEQ ID No. 57) wherein Xi, X2 and X3 are as defined for SEQ. ID. No. 56, and where "a" is selected from the group consisting of S, P, I, R, C, T, L, V, A, G, K, H, R, O, C, M, and F, or in another embodiment, is selected from the group consisting of, S, P, I, R, C, T, L, V, A, G, K, H, R, 0, C, and M, or in yet another embodiment, it is selected from the group consisting of, S, P, I, R, and C, or in yet another embodiment, S. In one embodiment, the isolated peptide comprises SEQ. ID. No. 57, or is a peptide of up to 10 amino acids comprising said sequence. In still another embodiment, the isolated peptide is SEQ. ID. Nos. 4, 47, or when this is a hexamer, the SEQ, ID. No. 39, or an isolated peptide of up to 10 amino acids comprising the sequences. In another embodiment, the isolated peptide of the invention comprises a peptide of the formula, "XiX2X3Pb" (SEQ ID No. 58) wherein XiX2X3 are as defined in SEQ. ID. DO NOT. 56 and "b" is selected from the group consisting of A, A *, G, S, L, F, K, C, I, V, T, Y, R, H, 0, and M, but in one embodiment it is not P, or in another modality it is selected from the group consisting of A, A *, G, S, L, F, and K, or in another modality, it is selected from the group consisting of A, A *, G, S, L, K and C, or in one embodiment is selected from the group consisting of A, A *, G, S, L, and K. Where A * denotes a D-amino acid of alanine. In one embodiment, the isolated peptide is an amino acid of up to 10 amino acids comprising SEQ. ID. No. 58. In one embodiment, the isolated peptide is or comprises SEQ. ID. Nos. 5-8, 10, 11, 13-16, 21-25, 27, 28, 31, 33-38 and 42-43. In yet another embodiment, the peptide is SEQ. ID. No. 58, where "b" is not P or Y, or not RIVPP (SEQ ID No. 17); or where X3 is not G or not RIGPA, or X3 or is Vx or not RIVxPA. In one embodiment, the isolated peptide of the invention is or comprises a peptide similar to SEQ. ID. No. 58, but where Xi is rather selected from the group consisting of G, GG, or Cit, or where "b" is A, X2 is I, X3 is V, Xi is G, GG, or Cit, or the peptide is SEQ. ID. Nos. 19, 20 and 36. In one embodiment, the isolated peptide is SEQ. ID. No. 31. In yet another embodiment, the isolated peptide comprises a reverse sequence of SEQ. ID. No. 58, or comprises SEQ. ID. No. 30. In one embodiment, the isolated peptide of the invention is or comprises the peptide having the amino acid sequence of SEQ. ID. No. 29. The peptide of the invention also provides an isolated peptide comprising the formula, "aia2 X1X2 3P" (SEQ ID No. 59), wherein Xi, X2 and X3 are as defined in SEQ. ID. No. 56 and ai is selected from the group consisting of K, IR, H, O, L, V, A, and G, or in one mode, K and I, or in a K mode and a2 is selected from the group that consists of S, P, RT, H, K, O, L, V, A, G, S, and I or in one mode, S, P, and R, or in another mode, S and P, or in another more mode, P. In one modality, ai is not acetylated, or where ai is K, K is not acetylated or is not SEQ. ID. No. 2. In one modality, the asylated peptide is or comprises SEQ. ID. Nos. 1, and 47 or a peptide of up to 10 amino acids comprising SEQ. ID. No. 59. In another embodiment, the isolated peptide of the invention is or comprises a peptide of the formula, "a X! X2X3Pb" (SEQ ID No. 60) wherein Xi, X2 and X3 are as defined in I KNOW THAT. ID. No. 56 and where "a" is selected from the group consisting of S, R, K, H, O, T, I, L, V, A, G or in another mode, S, R and I, or in another modality S and R, and wherein "b" is selected from the group consisting of A, V, I, L, G, K, H, R, O, S, T, F or in another more modality, A. In still another embodiment, the peptide of SEQ. ID. No. 60 is the SEQ. ID. Nos. 3, 12 and 39, or a peptide of up to 10 amino acids comprising SEQ. ID. No. 60 or SEQ. ID. Nos. 3, 12 or 39. As used herein, a "peptide comprising an amino acid sequence of Table 1" or a "peptide comprising an amino acid sequence of a sequence of Table 1" includes the peptide same, the obvious chemical equivalents for it, the isomers thereof (eg, isomers, stereoisomers, retro-isomers, retro-inverso isomers, isomers all- [D] isomers all- [L] or isomers [L] and [ D]), the conservative substitutions in the present, the precursor forms thereof, the endoproteolytically processed forms thereof, such as the cleavage of simple amino acids to starting from the N or C termini or the immunologically active metabolytes of the peptides of the invention, the pharmaceutically acceptable salts thereof and the asters thereof, and other forms resulting from the post-translational modification. Any progenitor sequence, up to and including 10, 9, 8, 7, 6, 5 and 4 amino acids in length (cyclized or linear, or branched from a core progenitor sequence), for which the specific sequence is also included, is also included. a subsequence. A person skilled in the art would appreciate that where the peptide in the table is a trimer, this could be a subsequence of 10, 9, 8, 7, 6, 5, and 4 mer, whereas if the peptide is listed in Table 1 is an exponent, this could be a subsequence of 10, 9, 8, and 7 mer, but not 5 or 4 mer. In addition, the invention comprises sequences that are more than 10 mer, SEQ. ID. Nos. 44 and 54. These modified peptides that preserve the immunological activity of the peptides of the invention are encompassed within the scope of the present invention. As used herein, an "obvious chemical equivalent" of a peptide of the invention is a molecule that possesses the same desired activity, e.g., immunological activity, such as the peptides described herein, and exhibits a different trivial chemical formula, or a molecule that is converted, under mild conditions, to a peptide of the invention (for example, esters, ethers, reduction products and complexes of the peptides of the invention). In addition, as used herein, "conservative substitutions" are those amino acid substitutions that are functionally equivalent to the substituted amino acid residue, either because they have similar polarity or a similar steric arrangement, or because they belong to the same class as the substituted residue (for example, hydrophobic, acid or base). The term "conservative substitutions", as defined herein, includes substitutions that have an effect without consequences on the ability of the peptide of the invention to increase innate immunity. Examples of conservative substitutions include the substitution of a polar (hydrophilic) residue for another (eg, arginine / lysine, glutamine / asparagine, or threonine / serine); the substitution of a non-polar (hydrophobic) residue (eg, isoleucine, leucine, methionine, phenylalanine, tyrosine, or valine) for another; the substitution of an acidic residue (for example, aspartic acid or glutamic acid) for another one; or the substitution of a basic residue (eg, arginine, histidine, lysine or ornithine) for another. The term "analog", as used herein, includes any peptide having an amino acid sequence substantially identical to a sequence described herein, in which at least one residue has been conservatively. An "analog" has 60% or more (preferably, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99%) of homology in the amino acid sequence with a amino acid sequence of Table 1, and is a functional variant thereof. As further used herein, the term "functional variant" refers to the activity of a peptide that demonstrates an ability to increase innate ability or reduce the activity of DPPIV, as described herein. An "analogue" includes a variant of an amino acid of Table 1 and has a homologous three-dimensional conformation. An "analog" further includes any pharmaceutically acceptable salt of an analog as described herein. A "variant" further includes any pharmaceutically acceptable salt of a variant as described herein. A "derivative", as used herein, refers to a peptide of the invention having one or more chemically derivatized amino acids by reaction of a functional side group. Exemplary derivatized molecules include, without limitation, peptide molecules in which free amino groups have been derivatized to form salts or amides, by the addition of acetyl groups, amine hydrochlorides, carbobenzoxy groups, chloroacetyl groups, formyl groups, p-groups -toluenesulfonyl or t-butyloxycarbonyl groups. The free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. In addition, free carboxyl groups can be derivatized to form salts, esters (for example, methyl and ethyl esters), or hydrazides. Thus, a "derivative" further includes any pharmaceutically acceptable salt of a derivative as described herein. In one embodiment of the present invention, the isolated peptide of the invention has a modified C-terminus and / or a modified N-terminus. For example, the isolated peptide may have an amidated C-terminus. For example, the amino terminus may be acetylated (Ac) or the carboxyl terminus may be amidated (NH2). However, in one embodiment of the invention, the peptides of the invention are not preferably acetylated if such modification could result in the loss of the desired immunological activity. Modifications at the amino terminus include methylation (for example, -NHCH3 or -NH (CH3) 2, acetylation, addition of a carbobenzoyl group, or blocking the amino terminus with a blocking group containing a carboxylate functional group defined by RC00-, where R is selected from the group consisting of the naphthyl, acridinyl, steroidyl and the like groups Modifications at the carboxyl terminus include the replacement of the free acid with a carboxamide group or the formation of a cyclic lactam in the carboxyl end, to introduce structural constraints. In one embodiment, substitutions to the main chain may be made, such as NH to NCH3. The isolated peptide may also be a modification (eg, a point mutation, such as an insertion or deletion, or a truncation) of or comprising an amino acid sequence of Table 1. By way of example, the peptide may comprise an amino acid sequence of Table 1 as modified by at least one point insertion of a D-amino acid as long as the desired immunological activity is preserved. In particular, proline analogs in which the ring size of the proline residue is changed from 5 members to 4, 6, or 7 members, can be employed. The cyclic groups can be saturated or unsaturated, and if saturated, they can be aromatic or non-aromatic. The side chains of natural origin of the 20 genetically encoded amino acids (D-amino acids) can be replaced with other side chains with similar properties, for example, with groups such as alkyl, lower alkyl, cyclic alkyl of 4-, 5-, 6 -, to 7 members, amide, amide- (lower alkyl), amide-di- (lower alkyl), lower alkoxy, hydroxyl, carboxyl, and the lower ester derivatives thereof, and with heterocycles from 4-, 5-, 6-, to 7- members. Such substitutions may include but are not necessarily limited to: (1) positively charged, non-standard amino acids, such as: ornithine, Dab; 2,4-diaminobutyric acid, which is like ornithine minus a methylene group (or the lysine minus two methylene groups), Dpr or Dapa; 2, 3-diaminopropionic acid, which is like ornithine minus two methylene groups (or the lysine minus three methylene groups) or the serine with an amino group instead of the hydroxyl), Nlys; N- (-aminobutyl) -glycine having the side chain of lysine linked to the "N-terminus", and the compounds with aminopropyl or aminoethyl groups linked to the amino group of glycine. (2), amino acids of non-natural origin such as arganine, without charge, such as, Cit; Citrulline and Hci; citrulline with one or more methylene groups; (3) amino acids of non-natural origin, non-standard with OH (eg, as serine), such as, hSer; homoserin (a further methylene group, Hyp; hydroxyproline, Val (betaOH); hydroxy valine, Pen; penicillamine, (Val (betaSH); (4) proline derivatives, such as, D-Pro, such as, 3, 4-dehydroproline , Pyr, pyroglutamine (proline with C = 0 in the ring), proline with fluorine substitutions in the ring, 1,3-thiazolidin-4-carboxylic acid (proline with S in the ring), (5) histidine derivative, such as, Thi; beta- (2-thienyl) -alanine; or (6) alkyl derivatives, such as, Abu; 2-aminobutyric acid (ethyl group on Calpha), Nva; norvaline (propyl group on Calpha), NIe; norleucine (butyl group on Calpha), Hol; homoleucine (propyl group on Calpha), Aib, alpha-aminoisobutyric acid (valine without the methylene group). A person skilled in the art could appreciate those substitutions that preserve the biological activity of the peptide / progenitor sequence. In another alternative embodiment, the C-terminal carboxyl group or a C-terminal ester can be induced to cyclize by internal displacement of the -OH or the ester (-OR) of the carboxyl group or the ester, respectively, with the amino group N -terminal to form a cyclic peptide. For example, after synthesis and cleavage to give the peptide acid, the free acid is converted to an activated ester by an appropriate carboxyl group activator, such as dicyclohexylcarbodiimide (DCC) in solution, for example, in methylene chloride (CH2C12). ), dimethylformamide (DF) and mixtures thereof. The cyclic peptide is then formed by internal displacement of the activated ester with the N-terminal amine. The internal cyclization in opposition to the polymerization can be increased by the use of highly diluted solutions. Such methods are well known in the art. The peptides of the invention can also be cyclized, or a deamino or decarboxyl residue incorporated in the ends of the peptide, so that there is no amino or carboxyl terminal group, to decrease the susceptibility to the proteases or to restrict the conformation of the peptide. The C-terminal functional groups of the compounds of the present invention include the amide, amide- (lower alkyl), amide-di (lower alkyl), lower alkoxy, hydroxyl, and carboxyl groups, and the lower ester derivatives thereof. , and the pharmaceutically acceptable salts thereof. The peptide can also be cyclized by adding an N- and / or C-terminal cysteine, and cyclizing the peptide through disulfide bonds or other side-chain interactions. An amino or decarboxyl residue may also be incorporated at the ends of the peptide, such that there is no amino or carboxyl terminal group, to decrease the susceptibility to the proteases or to restrict the conformation of the peptide.

Method of Making the Peptides The present invention contemplates the peptides, including the analogs, derivatives and peptide variants, which are produced synthetically, recombinantly generated or isolated from native cells. A peptide of the invention can be synthesized by methods commonly known to a person skilled in the art (eg, as described in Modern Techniques of Peptide and Amino Acid Analysis (New York: John Wiley &Sons, 1981; and Bodansky, M., Principies of Peptide Synthesis (New York : Springer-Verlag NY, Inc., 1984). Examples of methods that can be employed in the synthesis of the peptides of the invention include, but are not limited to, solid phase peptide synthesis, peptide synthesis by liquid method. or in solution, and synthesis using any of the commercially available peptide synthesizers In one embodiment, a peptide of the invention is synthesized in vitro, for example, by chemical means or in vitro translation of mRNA. the invention is produced recombinantly, using conventional techniques and the cDNA encoding the peptide The amino acid sequences of the present invention may further comprise coupling agents and protecting groups that are used in the synthesis of peptide sequences, and which are well known to a person skilled in the art. The analogs, derivatives and peptide variants of the invention can be made by a wide variety of different mutagenesis techniques well known to those skilled in the art. These techniques can be found in any laboratory manual of molecular biology, including, for example, Sambrook et al, Molecular Cloning -A Laboratory Manual, 2nd ed. (Plainview, NY: Cold Spring Harbor Press, 1989); or Ausubel et al, Current Protocols in Molecular Biology (John iley &Sons). Mutagenesis kits are also available from many commercial suppliers of molecular biology. Methods for performing site-directed mutagenesis, regiospecific or random in the initial amino acid sequence, are available. After the analogs, derivatives and variants are produced, they can be selected for the desired ability to increase innate immunity, as described herein.

Reagent Agents with Peptides The present invention further provides an agent reactive with a peptide comprising an amino acid sequence of TABLE 1 or an analog, derivative or variant thereof. As used herein, "reactive" means that the agent has an affinity for, binds to, or is directed against the peptide of the invention. As further used herein, an "agent" will include a protein, polypeptide, peptide, nucleic acid (including DNA or RNA), an antibody of non-natural origin, a Fab fragment, an F (ab ') 2 fragment, molecule , compound, antibiotic, drug, and any combination thereof.

A Fab fragment is a fragment of an antibody, univalent, that binds to the antigen, which is produced by digestion with papain. An F (ab ') 2 fragment is a fragment of an antibody, divalent antigen binding, which is produced by digestion with pepsin. Preferably, the agent of the present invention is labeled with a detectable label or label. An antibody of non-natural origin means an antibody that is generated with the peptide associated with another compound, such as two C-terminal glycine residues and MPAS. The MAPS antigen is linked to the peptide of the present invention via 2 glycine residues inserted at the C-terminus of the peptide. The construct can then be administered to an animal, such as a rabbit and the antibody harvested using methods well known in the art. In one embodiment of the present invention, the agent reactive with the peptide of the invention is an antibody. As used herein, the antibody of the present invention can be polyclonal or monoclonal. In addition, the antibody of the present invention can be produced by techniques well known to those skilled in the art. The polyclonal antibody, for example, can be produced by immunization of a mouse, rabbit or rat with a purified peptide of the invention. The monoclonal antibody can then be produced by removing the spleen of the immunized animal, and fusing the cells of the spleen with myeloma cells to form a hybridoma which, when grown in culture, will produce a monoclonal antibody. See, for example, J.G.R. Hurrel, Monoclonal Hybridoma Antibodies: Techniques and Applications (Boco Mouse, FL: CRC Press Inc., 1982). The antibody of the invention can be labeled with a detectable label or label. The labeling or labeling of an antibody can also be achieved using one of a variety of labeling techniques, including peroxidase, chemiluminescent labels known in the art, and radioactive labels known in the art. The detectable label or label of the present invention, for example, a non-radioactive or fluorescent label, such as biotin, fluorescein (FITC), acridine, cholesterol or carboxy-X-rhodamine, which can be detected using fluorescence and other forming techniques of images easily known in the art. Alternatively, the detectable label or label may be a radioactive label, including, for example, a radioisotope. The radioisotope can be any isotope that emits detectable radiation, such as 35S, 32P, 1251, 3H, or 14C. The radioactivity emitted by the radioisotopes can be detected by techniques well known in the art. For example, the gamma emission of the radioisotope can be detected using techniques of Gamma image formation, particularly formation of belt images. Preferably, the agent of the present invention is a high affinity antibody labeled with a detectable label or label.

Isolated Nucleic Acid Molecules In addition, the present invention provides an isolated nucleic acid molecule encoding a peptide comprising an amino acid sequence of TABLE 1 or an analog, derivative or variant thereof, including a conjugated peptide (e.g. a carrier-peptide construct) or other peptide, or a pro-peptide that metabolizes or breaks down an immunologically active peptide of TABLE 1. Due to the degeneracy of the genetic code, the nucleic acid molecule of the invention includes a plurality of substitutions. of nucleic acids that will also code for a peptide of the invention. The present invention further provides a nucleic acid that hybridizes to the isolated nucleic acid molecule, which encodes an amino acid sequence of TABLE 1 or an analog, derivative or variant thereof. The nucleic acid molecules of the present invention may be DNA or RNA. These can be prepared by a variety of techniques known to those experts in the field including, without limitation, automated synthesis of oligonucleotides using commercially available oligonucleotide synthesizers, such as the Applied Biosystems Model 392 DNA / RNA synthesizer. In addition, the nucleic acid molecules of the present invention can be labeled with one or more detectable markers. The labeling of the nucleic acid molecules can be achieved using one of a number of methods known in the art-for example, pseudo-translation, end-labeling, end-labeling, polynucleotide-kinase exchange reaction, random priming, or SP6 -polymerase (for the preparation of the riboprobe) - together with any of a variety of markers-for example, radioactive markers such as 35S, 32P, or 3H, or non-radioactive markers such as biotin, fluorescein (FITC), acridine, cholesterol , or carboxy-X-rhodamine (ROX). The present invention also provides a recombinant nucleic acid construct comprising a nucleic acid molecule of the invention operably linked to an expression vector. As used herein, an "expression vector" is a DNA construct that contains a DNA sequence that is operably linked to a suitable control sequence capable of effecting expression of the DNA in a suitable host. He vector can be, for example, a plasmid, a phage particle, or a potential genomic insert. As further used herein, the term "operably linked" describes a functional relationship between the two regions of AD. Expression vectors suitable for use in the present invention comprise at least one expression control element (eg, operator, promoter, lac system, leader sequence, termination codon and / or polyadenylation signal) operably linked to the molecule of nucleic acid encoding a peptide of the invention. In one embodiment, the expression vector is a eukaryotic expression vector that functions in eukaryotic cells (e.g., a retroviral vector, a vaccinia virus vector, an adenoviral vector, a herpes virus vector, or a vector of the eukaryotic vector). avian pox virus). Once operably linked to a nucleic acid molecule of the invention, the expression vector can be introduced into a recipient cell by any of the in vivo or ex vivo media suitable for nucleic acid transfer, including, without limitation, electroporation , transfection with DEAE-dextran, transfection with calcium phosphate, lipofection, monocationic liposome fusion, polycationic liposome fusion, protoplast fusion, creation of an electric field in vivo, bombardment with microprojectiles coated with DNA, injection with recombinant viruses defective in replication, homologous recombination, viral vectors, naked DNA transfer, or any combination thereof. Recombinant viral vectors suitable for the transfer of the nucleic acid include, but are not limited to, vectors derived from the genomes of viruses such as retroviruses, HSVs, adenoviruses, adeno-associated viruses, Semiliki Forest viruses, cytomegalovirus, and viruses of the vaccinia The present invention further provides at least one host cell comprising the recombinant nucleic acid construct of the invention. The host cell of the invention is transformed with the nucleic acid construct described herein. The host cell can be eukaryotic (e.g., an animal, plant, insect or yeast cell) or prokaryotic (e.g., E. coli). In addition, the present invention provides a method for producing a peptide comprising an amino acid sequence of TABLE 1 or an analog, derivative or variant thereof. The method comprises the steps of: (a) culturing at least one host cell comprising a recombinant nucleic acid construct, as described herein, under conditions that allow expression of the peptide; and (b) recovering the peptide from at least one host cell or from the culture medium thereof. The recombinant peptide can be recovered as a crude lysate; this can be purified by standard protein purification procedures, known in the art, without limitation, affinity and immunoaffinity chromatography, differential precipitation, gel electrophoresis, ion exchange chromatography, isoelectric focusing chromatography and size exclusion, and the like.

Pharmaceutical Composition The present invention further provides a pharmaceutical composition comprising a peptide including an amino acid sequence of TABLE 1 or SEQ ID Nos. 1, 3-16 or 18-60, or an analog, derivative or variant thereof ( which includes a pharmaceutically acceptable salt, salt by addition of acid or ester of any of the foregoing), in combination with at least one pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutically acceptable carrier, diluent or excipient may be "acceptable" in the sense of being compatible with the other ingredients of the composition, and not harmful to the container thereof. Examples of pharmaceutically acceptable carriers, diluents and excipients include, without limitation, carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. The formulations of the The pharmaceutical composition of the invention as described herein, can conveniently be presented in unit dose.

Uses The peptides of the invention have been shown to have therapeutic utility in enhancing innate immunity. The increase or improvement of innate immunity is demonstrated by the lack of antimicrobial activity (Example 2) and protection against infection in in vivo models (Examples 3 and 4) and also by DPPIV assays of Example 5. Accordingly, the present invention also provides a method for treating and / or preventing infection in a subject. As used herein, the "subject" is a bird (e.g., a chicken, turkey, etc.) or a mammal (e.g., a cow, dog, human, monkey, mouse, pig, rat, etc.). ). In one modality, the subject is a human. The subject may have, or be at risk of having, an infection. As an example, the infection can be a microbial infection. Microbial infections that can be treated by the method of the present invention include, without limitation, infection by a bacterium, infection by a fungus, infection by a parasite and infection by a virus. The majority of bacterial pathogens are present in the general environment, or in the normal bacterial flora of the host. Bacteria have evolved the ability to cause severe disease by acquiring different mechanisms (called virulence factors) that enable them to colonize, spread within and invade host tissues. When these pathogenicity factors are suppressed, the bacteria are no longer able to maintain themselves in the tissues of the host and therefore, can not cause disease. Exemplary bacteria that can be treated by the method of the present invention include, without limitation, E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp. (for example, Salmonella typhimurium), Staphylococcus aureus, Streptococcus spp. , and vancomycin-resistant enterococci. Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium that is noted for its environmental versatility, its ability to cause disease in susceptible individuals, and its resistance to antibiotics. This is a versatile organism that develops in the soil, marshes and coastal marine habitats, and in plant and animal tissues. The most serious complication of cystic fibrosis is the infection of the respiratory tract by P. aerugínosa. Patients with cancer and burns also commonly suffer serious infections from this organism, as they also suffer from other certain individuals with deficiencies of the immune system. Contrary to many environmental bacteria, P. aeruginosa has a remarkable ability to cause disease in susceptible hosts. Staphylococcus aureus is a spherical bacterium Gram-positive, approximately 1 micrometer in diameter, which thrives in microscopic groups. This is one of the most important human pathogens, causing nosocomial infections and acquired in the community, ranging from endocarditis to pneumonia. Although S. aureus is generally classified as an extracellular pathogen, recent data have revealed its ability to infect various host cell types, for example, professional phagocytes and non-phagocytes, including endothelial cells, fibroblasts and others. This invasion is initiated by the adhesion of S. aureus to the cell surface, a process in which staphylococcal fibronectin binding proteins play a prominent role. S. aureus phagocytosis can induce either apoptosis of the host cell or survive for several days in the cytoplasm - which is thought to be devoid of anti-staphylococcal effector mechanisms. S. aureus colonizes the nasal passages, the surfaces of the skin, the mucous membranes, and the areas around the mouth, the genitals and the rectum. S. aureus It can cause superficial skin lesions, such as infarcted lymph nodes, styes and boils. More serious infections include pneumonia, mastitis, phlebitis, meningitis, and urinary tract infections; Deep seated infections include osteomyelitis and endocarditis. Exemplary fungi that can be treated by the method of the present invention include, without limitation, molds, yeasts, and higher fungi. All fungi are eukaryotic, and have sterols, but not peptidoglycan, in their cell membranes. Fungal infections, or mycoses, are classified according to the degree of tissue involvement and the mode of entry to the host. In the immunocompromised host, a variety of nonpathogenic fungi, or fungi that are usually mild, can cause potentially fatal infections. Parasites are organisms that derive nutrients and protection from other living organisms (known as hosts). These can be transmitted from animals to humans, from humans to humans, or from humans to animals. Several parasites have emerged as significant causes of diseases carried by food and carried by water. These can be transmitted from host to host through the consumption of contaminated food and water, or through the ingestion of a substance that has come into contact with the excrement (feces) of a person or animal infected. Parasites live and reproduce within the tissues and organs of infected human and animal hosts, and are often excreted in the feces. There are different types of parasites, ranging from small, unicellular, microscopic organisms (protozoa) to larger, multicellular worms (helminths) that can be observed without a microscope. Examples of common parasites that can be treated by the method of the present invention include, without limitation, Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis and Toxoplasma gondii. Viruses are, contrary to fungi and bacteria, lacking many of the attributes of free-living cells. A simple viral particle is a static structure, very stable and unable to change or replace its parts. Only when it is associated with a cell does a virus become capable of replicating itself and acquiring some of the attributes of a living system. Viruses can cause numerous diseases, including upper respiratory tract infections (URTIs) such as the common cold and pharyngitis (inflamed throat). Other examples of viruses that can be treated by the method of the present invention include, without limitation, viruses associated with AIDS, avian influenza, chicken pox, cold sores, common cold, gastroenteritis (especially in children), glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower respiratory tract infections (eg, respiratory syncytial virus, or RSV). The inventors have demonstrated herein that the peptides comprising the amino acid sequence of TABLE 1 or SEQ ID NOs: 1, 3-16, 18-60, or the analog, derivative or variant thereof or the chemical equivalent obvious of them are effective in the prevention and / or treatment of the infection. Accordingly, the present method of treating and / or preventing infection in a subject, comprises administering to the subject a peptide comprising the amino acid sequence of TABLE 1 or SEQ ID NO: 1, 3-16, 18-60 , or the analog, derivative or variant thereof or the obvious chemical equivalent thereof. It is within the confines of the present invention that the peptide of the invention can be linked to another agent or administered in combination with another agent, such as an antibiotic (eg, penicillin, methicillin or vancomycin), in order to increase the effectiveness of the treatment and / or prevention of the infection and / or the increase of the effectiveness of the direction to the objective. In one embodiment of the present invention, the peptide of the invention comprises the amino acid sequence of TABLE 1 or SEQ ID NO: 1, 3-16, 18-60, or the analog, derivative or variant thereof or the chemical equivalent obvious of it. In another embodiment, the peptide of the invention modulates the innate immunity in the subject, thereby treating and / or preventing infection in the subject. The innate immune response is the frontal line response to an encounter with the pathogen. This comprises a plurality of mechanisms to prevent the development of the infectious disease. A mechanism of this type involves the recruitment and recruitment of immune effector cells. In one embodiment, the peptides of the invention can increase the innate immunity or the innate immune response, while limiting inflammation. In another embodiment, the peptides of the invention have been shown to be modulators of DPPIV activity. These have been shown to reduce the activity of DPPIV. As such, they could be useful in the selection of subjects who can benefit from the administration of the peptides to treat a particular immunological condition, which comprises taking a sample from a suspect subject or one known to have a DPPIV-related condition, incubating it together with a peptide of the invention and a DPPIV substrate, and then monitoring the effect of the peptide on the activity of DDPIV compared to a control, wherein a reduction in activity could indicate the potential benefit of the administration of the peptide to the subject for treat a condition related to DPPIV. In still another embodiment of the DPPIV activity in the presence of the peptide compared to the control, it may be an indicator of a condition related to DPPIV. As such, the peptides of the invention can be used in the diagnosis of conditions related to DPPIV. In yet another aspect, the peptides of the invention could be useful in the treatment of a number of immunological disorders, such as DPPIV-related disorder, such as: HIV / AIDS, Grave's disease, cancer (such as lung and lung cancer). colon), diabetes, and autoimmune disorders such as rheumatoid arthritis and multiple sclerosis.

Administration In accordance with the method of the present invention, a peptide of the present invention as described herein can be administered to the subject directly, in an amount effective to treat and / or prevent infection in the subject and or to treat or prevent a condition related to DPPIV, for example a therapeutically effective amount. Similarly, a peptide as described herein can be administered to the subject indirectly, by administering to the subject a nucleic acid sequence encoding the peptide, in a manner that allows expression of the peptide in the subject, and in a effective amount to treat and / or prevent infection. In addition, a peptide of the invention, or a nucleic acid molecule encoding the same, can be administered to a subject in an amount effective to treat the infection in the subject. As used herein, the phrase "effective to treat the infection" means effective to improve or minimize clinical deterioration or symptoms resulting from infection (by a bacterium, fungus, parasite, virus, etc.). For example, where the subject is infected with a microbe, the amount of the peptide (or the nucleic acid encoding it) that is effective in treating the microbial infection is that which can improve or minimize the symptoms of the infection. microbial, including, without limitation, headache, stiff neck, anorexia, nausea, vomiting, diarrhea, abdominal discomfort, acute renal failure, changing manifestations of ischemic damage to multiple organs, fever and thrombocytopenia. The amount of the peptide (or the nucleic acid encoding it) effective to treat an infection in a subject will vary depending on the particular factors of each case, including the subject's weight and the severity of the subject's condition. The appropriate amount of the peptide (or the nucleic acid encoding it) can be easily determined by the person skilled in the art. Similarly, the effective amount to treat a condition related to DPPIV may vary depending on a number of similar factors known to a person skilled in the art. Similarly, in the method of the present invention, a peptide of the invention, or a nucleic acid molecule encoding the same, can also be administered to a subject at risk of developing an infection, in an amount effective to prevent infection in the subject. As used herein, the phrase "effective to prevent infection" includes effective or effective to prevent or prevent the development or manifestation of clinical deterioration or symptoms resulting from infection (by a bacterium, fungus, parasite, virus, etc.) . The amount of peptide (or the nucleic acid encoding it) effective to prevent infection in a subject will vary depending on the particular factors of each case, including the sex of the subject, the weight and the severity of the subject's condition. , the nature of the condition, the site of the infection and the mode of administration. The appropriate amount of the peptide (or the nucleic acid encoding it) can be easily determined by the person skilled in the art. The peptide of the invention, or the nucleic acid sequence encoding it, as described herein, can be administered to a human or animal subject. by known methods including, without limitation, oral administration, parenteral administration (e.g., epiphasic, intracapsular, intracutaneous, intradermal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, parenchymal, or subsequent), transdermal administration , intranasal administration, pulmonary administration (for example, intratracheal administration), and administration by osmotic pump. In one embodiment, the method of administration is parenteral administration, by intravenous and subcutaneous injection. For oral administration, the formulation of the peptide (or the nucleic acid encoding it) can be presented as capsules, tablets, powders, granules or as a suspension or liquid. The formulation may have conventional additives such as lactose, mannitol, corn starch or potato starch. The formulation can also be presented with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin. In addition, the formulation may be presented with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose. The formulation may also be presented with anhydrous calcium dibasic phosphate or sodium starch glycolate. Finally, the formulation can be presented with lubricants, such as talc or magnesium stearate. For parenteral administration, the peptide (or the nucleic acid encoding the same) can be combined with a sterile aqueous solution, which is preferably isotonic with the subject's blood. Such a formulation may be prepared by dissolving a solid active ingredient in water containing physiologically compatible substances, such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions, to thereby produce an aqueous solution. , making then sterile to said solution. The formulation may be presented in unit dose or multi-dose containers, such as sealed vials or vials. The formulation can also be delivered by any mode of injection, including any of those described herein. For transdermal administration, the peptide (or the nucleic acid encoding the same) can be combined with cutaneous penetration enhancers, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone and the like, which increase the permeability of the skin to the peptide or nucleic acid, and allow the peptide or nucleic acid to penetrate through the skin or into the bloodstream. The composition of the enhancer and the peptide or nucleic acid can also be further combined with a polymeric substance, such as ethylcellulose, hydroxypropylcellulose, ethylene / vinyl acetate, polyvinylpyrrolidone and the like, to provide the composition in gel form, which can be dissolved in solvent, such as methylene chloride, evaporated to the desired viscosity, and then applied to the backing material to provide a patch. The peptide or nucleic acid may be administered transdermally, at or near the site on the subject where the infection may be located. Alternatively, the peptide or nucleic acid can be administered transdermally at a site different from the affected area, in order to achieve systemic administration. For intranasal administration (eg, nasal sprays) and / or pulmonary administration (administration by inhalation), formulations of the peptide or nucleic acid, including aerosol formulations, can be prepared according to well-known procedures for Expert people in the field. The aerosol formulations may comprise solid particles or solutions (aqueous or non-aqueous). Nebulizers (e.g., jet nebulizers, ultrasonic nebulizers, etc.) and atomizers can be used to produce aerosols from solutions (e.g., using a solvent such as ethanol); the Metered dose inhalers and dry powder inhalers can also be used to generate small particle aerosols. The desired particle size of the aerosol can be obtained by employing any of a number of methods known in the art, including, without limitation, jet milling, spray drying, and critical point condensation. Pharmaceutical compositions for intranasal administration can be solid formulations (e.g., a coarse powder), and may contain excipients (e.g., lactose). Solid formulations can be administered from a powder container brought up to the nose, using rapid inhalation through the nasal passages. The compositions for intranasal administration may also comprise aqueous or oily solutions of nasal spray or nasal drops. For use with a sprayer, the peptide or nucleic acid formulation may comprise an aqueous solution and additional agents, including, for example, an excipient, a buffer, an isotonicity agent, a preservative or a surfactant. A nasal spray can be produced, for example, by forcing a suspension or solution of the peptide or nucleic acid through a nozzle under pressure. Peptide or nucleic acid formulations for pulmonary administration can be presented in a form suitable for distribution by an inhalation device, and may have an effective particle size to reach the lower airways of the lungs or sinuses. For absorption through the mucosal surfaces, including the pulmonary mucosa, the formulation of the present invention may comprise an emulsion including, for example, a bioactive peptide, a plurality of submicron particles, a mucoadhesive macromolecule and / or a continuous phase watery The absorption through the mucosal surfaces can be achieved through the mucoadhesion of the emulsion particles. The pharmaceutical compositions for use with a metered dose inhaler device may include a finely divided powder containing the peptide or the nucleic acid as a suspension in a non-aqueous medium. For example, the peptide or nucleic acid can be suspended in a propellant with the aid of a surfactant (for example, sorbitan trioleate, soy lecithin, or oleic acid). The metered dose inhalers typically utilize a propellant gas (e.g., a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon) stored in a container (e.g., a can) as a mixture (e.g., as a liquefied or compressed). Inhalers require activation during inspiration. By For example, the actuation of a measuring valve can release the mixture as an aerosol. Dry powder inhalers use breathing action of a mixed powder. The peptide or nucleic acid of the present invention can also be released or distributed from an osmotic minipump or other synchronized delivery device. The release rate from an elementary osmotic minipump can be modulated with a rapid, microporous response gel, placed in the release orifice. An osmotic minipump could be useful for controlling the release or targeted distribution of the peptide or nucleic acid. In accordance with the methods described herein, the peptide of the invention can be administered to a subject by introducing the peptide itself into the subject, or by introducing a nucleic acid encoding the peptide into the subject, in a manner that allows expression of the peptide. Accordingly, in one embodiment of the present invention, infection in a subject can be treated or prevented by administering to the subject an amount of a peptide of the invention. In a further embodiment of the present invention, infection in the subject can be treated or prevented by administering to the subject a nucleic acid sequence encoding the peptide of the invention, from a way that allows the expression of the peptide in the subject. The peptides of the present invention can be administered and introduced to a subject by known techniques used for the introduction of proteins and other drugs, including, for example, injection and transfusion. Where an infection is localized to a particular portion of the subject's body, it may be desirable to introduce the therapeutic peptide directly to the area by injection or by some other means (for example, by introducing the peptide into the blood or other body fluid). The amount of the peptide to be used is an amount effective to treat and / or prevent infection in the subject, as defined above, and can be readily determined by the person skilled in the art. In the method of the present invention, the peptide can also be administered or introduced to the subject by introducing into a scient number of cells of the subject, a nucleic acid encoding the peptide, in a manner that allows expression of the peptide. The amount of the nucleic acid encoding the therapeutic peptide is an amount that will produce the peptide in an amount effective to treat and / or prevent infection, as defined above, in the subject. This amount can be easily determined by the person skilled in the art.

The nucleic acid encoding the peptide of the present invention can be introduced into the subject using standard procedures known in the art, including, without limitation, electroporation, infection with DEAE-dextran, calcium phosphate transfection, lipofection, fusion of monocationic liposome , fusion of polycationic liposome, fusion of protoplasts, creation of an electric field in vivo, bombardment with microprojectiles coated with DNA, injection with defective viruses in recombinant replication, homologous recombination, gene therapy in vivo, ex vivo gene therapy, viral vectors, naked DNA transfer, or any combination thereof. Recombinant viral vectors suitable for gene therapy include, but are not limited to, vectors derived from the genomes of viruses such as retroviruses, HSV, adenovirus, adeno-associated virus, Semiliki Forest virus, cytomegalovirus and vaccinia virus. It is also within the confines of the present invention that a nucleic acid encoding a peptide can be introduced into suitable cells in vitro, using conventional methods, to achieve expression of the therapeutic peptide in the cells. Cells expressing the peptide can then be introduced into a subject to treat and / or prevent infection in vivo. In such an ex vivo gene therapy procedure, the cells are preferably removed from the subject, subjected to DNA techniques to incorporate the nucleic acid encoding the therapeutic peptide, and then reintroduced to the subject. It is also within the confines of the present invention that a formulation containing a peptide of the invention, or a nucleic acid encoding thereto, can be further associated with a pharmaceutically acceptable carrier, diluent or excipient, thereby comprising a pharmaceutical composition. The pharmaceutical compositions of the invention and the exemplary carriers, diluents and excipients are described above. The formulations of the present invention can be prepared by methods well known in the pharmaceutical arts. For example, the peptide of the invention, or a nucleic acid encoding it, can be put in association with a carrier, diluent or excipient, such as a suspension or solution. Optionally, one or more accessory ingredients (e.g., brs, flavoring agents, surface active agents, and the like) may also be added. The choice of the carrier will depend on the administration route. The pharmaceutical composition could be useful for administering the peptide of the present invention, or a nucleic acid molecule encoding the same, to a subject, for the purpose of to treat and / or prevent infection. The peptide or nucleic acid is provided in an amount effective to treat and / or prevent infection in a subject, to whom the pharmaceutical composition is administered. This amount can easily be determined by the person skilled in the art, as described above.

Diagnostic and Selection Assays The present invention provides a method for diagnosing a subject suspected of having an innate immune condition, or condition related to DPPIV, to predict whether a subject may or may not respond to treatment with a peptide of the invention, such as those listed in TABLE 1, or an analog, derivative or variant thereof, and to select agents that could modulate (e.g., augment, inhibit or mimic) the immunological effect of the peptides of the invention. In another embodiment, the invention provides methods for selecting the immunologically active analogs, derivatives and variants of the peptides of the invention or those listed in TABLE I or the immunologically active modifications thereof. In one embodiment, a method for predicting whether a patient with an immunological disorder, such as an innate condition related to the immune system, could respond or not to treatment with a peptide of the invention, comprises obtaining a biological sample from the subject, administering a peptide of the invention to the sample, and monitoring the levels of a predetermined marker, which is an indicator of the condition, such as DPPIV for a condition related to DPPIV, an inflammatory biomarker for an infection, cell viability or bacterial load, compared to a positive and / or negative control. The positive control can be a sample from a subject with a known immunological condition. A negative control can be a sample from the same subject to which the peptide has not been administered. If the peptide modulates the activity, the level of marker, or the cell viability in relation to the control, the subject may have such immunological disorder and may benefit from treatment with the peptide. More particularly, in one aspect of the invention, if the subject has or is suspected of having a condition related to DPPIV, then monitoring the activity of DPPIV as the marker for the condition would be appropriate. In one aspect, the reduction of DPPIV activity compared to the control could be an indicator that the subject would respond to treatment with the peptide. Alternatively, if the subject has or was suspected of having an infection, then obtaining a patient sample, the monitoring of this for a pathogen load or cell viability in comparison to a sample from the patient after the administration of the peptide, where the load of the pathogen is lower or the cell viability is higher in the patient after the administration of the peptide, is an indicator that the subject could benefit from treatment with the peptide or has an immunological disorder. In yet another embodiment, if it is desired to see whether a peptide or modification of a TABLE 1 peptide or other agent could have the same immunological activity of the peptide of the invention, the effect of the peptide on the activity of DPPIV in the comparison to the reference peptide with known modulatory effects, on a sample (either from a mouse infected with an agent or a known condition related to DPPIV), or to monitor the prevention, administration of the peptide or agent to a sample, the induction of the infection or condition related to DPPIV in the sample, and then monitoring whether the peptide modulated or inhibited the development of the infection or condition related to DPPIV, or the immune response. Said sample can be an animal model, where the induction of the condition or infection is carried out in an accepted animal model, in accordance with the ethical guidelines and then the animal or the sampleThe biological activity of the animal is selected for the effect of the peptide. The present invention further provides a method for predicting whether or not a subject could respond to treatment for a microbial infection, wherein the treatment comprises administering to the subject a peptide comprising an amino acid sequence of TABLE 1 or an analog, derivative or variant thereof. The method includes the evaluation of a diagnostic sample of the subject for one or more biomarkers (such as an inflammatory biomarker), wherein the presence of at least one biomarker (such as an inflammatory biomarker) is indicative that the subject could respond to the treatment. As used herein a "biomarker" or "label" is any suitable biomarker that is known, or is recognized to be related to the condition (e.g., immune condition, infection, inflammatory condition, condition related to DPPIV, immune condition). innate), and includes any molecule derived from a gene (eg, a transcript of the gene), a sense (coding) or antisense (non-coding) probe sequence derived from a gene, or a translation product of partial length or full length of a gene, or an antibody to it, that can be used to monitor a condition, disorder or disease associated with the immune response, the response innate immune, inflammation and / or a condition related to DPPIV. According to the method of the present invention, the diagnostic sample of a subject can be evaluated in vitro or in vivo. Where the assay is performed in vitro, a diagnostic sample of the subject can be removed using standard procedures. The diagnostic sample can be tissue, including any muscle tissue, skin tissue, or soft tissue, which can be removed by standard biopsy. In addition, the diagnostic sample can be a bodily fluid, including blood, saliva, serum or urine. It can be known that the subject or patient has a microbial infection or other immunological disorder such as a condition related to DPPIV, suspected of having a microbial infection or other immunological condition, such as an innate immune condition or condition related to DPPIV, or that is he believes he does not possess a microbial infection or other immunological condition, such as an innate immune condition, or the condition related to DPPIV. According to the method of the present invention, a diagnostic sample of the subject can be evaluated for the expression of one or more desired markers. As used herein, "expression" means the transcription of an inflammatory marker gene within the minus a transcript of mRNA, or the translation of at least one mRNA into a marker protein. Consequently, a diagnostic sample can be evaluated for marker expression when evaluating a marker protein, cDNA marker, or marker mRNA. The appropriate form of the marker will be apparent based on the particular techniques discussed herein. The protein to be evaluated can be isolated and purified from the diagnostic sample of the subject or the patient using standard methods known in the art, including without limitation, extraction from a tissue (for example, with a detergent that solubilizes the protein) where necessary, followed by affinity purification on a column, chromatography (e.g., FPLC and HPLC), immunoprecipitation (with an antibody to an inflammatory marker of interest), and precipitation (e.g., with isopropanol and a reagent such as Trizol ). The isolation and purification of the protein can be followed by electrophoresis (for example, on an SDS-polyacrylamide gel). It is contemplated that the diagnostic sample may be evaluated for the expression of any or all of the forms of the marker protein (including the endoproteolytically processed precursor forms, and other forms resulting from the post-translational modification). The nucleic acid can be isolated from a diagnostic sample using standard techniques known to a person skilled in the art. According to the method of the present invention, a diagnostic sample of a subject can be evaluated for the expression of the marker, and the expression of the marker can be detected in a diagnostic sample, using assays and detection methods easily determined from of the known technique (e.g., immunological techniques, hybridization analysis, fluorescence imaging techniques, and / or radiation detection), as well as any assays and detection methods described herein (e.g., immunoprecipitation, analysis by Western transfer, etc.). For example, a diagnostic sample of a subject can be evaluated for marker expression using an agent reactive with an inflammatory marker. As used herein, "reactive" means that the agent has affinity for, binds to, or is directed against the marker. As further used herein, an "agent" will include a protein, polypeptide, peptide, nucleic acid (including DNA or RNA), antibody, Fab fragment, F (ab ') 2 fragment, molecule, compound, antibiotic, drug and any combination or combinations thereof. Preferably, the agent of the present invention is labeled with a detectable label or label, according to techniques described in the present. In one embodiment of the present invention, the agent reactive with a label is an antibody. Where the agent of the present invention is an antibody reactive with the desired marker, a diagnostic sample taken from the subject can be purified by passage through an affinity column containing the antibody to the label, bound as a ligand to a solid support (for example, an insoluble organic polymer in the form of a sphere, gel or plate). The antibody bound to the solid support can be used in the form of a column. Examples of suitable solid supports include, without limitation, agarose, cellulose, dextran, polyacrylamide, polystyrene, sepharose and other insoluble organic polymers. The antibody for the label can also be linked to the solid support through a spacer molecule, if desired. The appropriate binding conditions (eg, temperature, pH, and salt concentration) to ensure the binding of the agent and the antibody can be easily determined by the person skilled in the art. In a preferred embodiment, the antibody for the label is linked to a sepharose column, such as Sepharose 4B. In addition, where the agent is an antibody, a diagnostic sample of the subject can be evaluated for the expression of the immunological marker using studies of linkage using one or more immunoreactive antibodies with the marker, together with standard immunological detection techniques. For example, the marker protein, eluted from the affinity column can be subjected to an ELISA assay, Western blot analysis, flow cytometry, or any other method of immunostaining using an antigen-antibody interaction.

Preferably, the diagnostic sample is evaluated for the expression of the marker using Western blot. Alternatively, a diagnostic sample from a subject can be evaluated for marker expression using hybridization analysis of the nucleic acid extracted from the diagnostic sample taken from the subject. According to this method of the present invention, hybridization analysis can be conducted using the Northern blot analysis of the mRNA. This method can also be conducted by performing a Southern analysis of the DNA, using one or more nucleic acid probes that hybridize to the nucleic acid encoding the marker. Nucleic acid probes can be prepared by a variety of techniques known to those skilled in the art, including, without limitation, the following: digestion with acid restriction enzymes marker nucleic acid; and automated synthesis of oligonucleotides having sequences corresponding to the selected portions of the nucleotide sequence of the marker nucleic acid, using commercially available oligonucleotide synthesizers, such as the Applied Biosystems Model 392 DNA / RNA synthesizer. The nucleic acid probes used in The present invention may be DNA or RNA, and may vary in length from about 8 nucleotides to the full length of the inflammatory marker nucleic acid. In addition, the nucleic acid probes of the present invention can be labeled with one or more detectable labels or labels. The labeling of the nucleic acid probes can be carried out using one of a number of methods known in the art, including any of those described herein. Combinations of two or more nucleic acid probes (or primers), corresponding to different or overlapping regions of the marker nucleic acid, can also be used to evaluate a diagnostic sample for marker expression, using, for example, PCR or RT -PCR The detection of marker expression in the method of the present invention can be followed by an assay to measure or quantify the degree of expression of the label in a diagnostic sample from a subject.

Such assays are well known to a person skilled in the art, and may include immunoassay / immunocytochemistry, flow cytometry, mass spectroscopy, Western blot analysis, or an ELISA to measure the amounts of the marker protein. For example, to use an immunohistochemistry assay, the histological (paraffin-embedded) sections of the tissue can be placed on slides, and then incubated with an antibody against a marker. The slides can be incubated with a second antibody (against the primary antibody), which is labeled for a dye or other calorimetric system (for example a fluorochrome, a radioactive agent, or an agent that contains high electron scanning capacity) to allow the display of the marker present in the sections. The present invention is described in the following Examples, which are described to help understand the invention, and should not be considered as limiting in any way the scope of the invention as defined in the claims that follow below.

EXAMPLES EXAMPLE 1 - SYNTHESIS OF PEPTIDES The peptides in TABLE 1 were synthesized using a solid phase peptide synthesis technique. All the Fmoc protected amino acids, required, were weighed in a triple molar excess relative to 1 mmol of the desired peptide. The amino acids were then dissolved in dimethylformamide (DMF) (7.5 ml) to make a solution of 3 mmol. The appropriate amount of Rink amide MBHA resin was weighed taking into account the substitution of the resin. The resin was then transferred to the reaction vessel of the automated synthesizer and pre-moistened with dichloromethane (DCM) for 15 minutes. The resin was deprotected by the addition of 25% piperidine in DMF (30 ml) to the resin, and mixing for 20 minutes. After deprotection of the resin, the first coupling was carried out by mixing the solution of the amino acid 3 mMol with 4 mMol of 2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate ( HBTU) and 8 mMol of N, N-diisopropylethylamine (DIEPA). The solution was left preactivated for 5 minutes before being added to the resin. The amino acid was allowed to attach for 45 minutes. After the coupling the resin was perfectly rinsed with DMF and dimethylacetamide (DMA). The amino acid protected with Fmoc, bound, was deprotected in the same manner as described above and the following amino acid was linked using the same coupling scheme AA: HBTU: DIEPA. After the completion of the synthesis, the peptide was cleaved from the resin with the use of a cleavage cocktail containing 97.5% trifluoroacetic acid (TFA) and 2.5% water. The resin was allowed to swim in the cleavage cocktail for 1.5 hours. The solution was then filtered by gravity using a Buchner funnel and the filtrate was collected in a 50 ml centrifuge tube. The peptide was isolated by precipitation with cooled diethyl ether. After centrifugation, and decanting the diethyl ether the crude peptide was washed with diethyl ether once again before being dried in a vacuum desiccator for 2 hours. The peptide was then dissolved in deionized water (10 ml), frozen at -80 ° C and lyophilized. The dried peptide was then ready for purification by HPLC. Due to the hydrophilic nature of these peptides, the isolation of the peptide with diethyl ether did not work. Therefore, extraction with chloroform was required. The TFA was evaporated and the resulting peptide residue was dissolved in 15 ml of 10% acetic acid. The impurities and scrubbers were removed from the Acetic acid peptide solution by washing the solution twice with 30 ml of chloroform. The aqueous peptide solution was then frozen at -80 ° C and lyophilized, resulting in a powder peptide ready for purification by HPLC. The peptides of SEQ ID NOs: 33 and 34 each contained an N-methyl-amino acid. This coupling was carried out by combining the N-methyl-amino acid, PyBroP and N-hydroxybenzotriazole * H20 (HOBt) and DIEPA solutions together in RV containing the resin. After allowing to couple for 45 minutes the N-methyl-amino acid was then doubly coupled to ensure complete coupling. It was observed that the coupling after N-methyl amino was not complete. Therefore, this coupling was performed using β, β, β ', β' - tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU) instead of HBTU. This still resulted in a crude peptide typically containing two impurities totaling 30-40% of the total purity. The peptide was purified under modified HPLC conditions to isolate the pure peptide peak from the impurities eluting closely EXAMPL09 2 - NON-ANTIMICROBIAL ACTIVITY Bacteria (S. aureus 25923) were seeded into wells containing the peptide (200 μ?), Vehicle (Tris), or antibiotic (erythromycin, 120 g / ml). The bacteria were allowed to develop for 2 hours. After this, bacterial viability was determined using a WST-1 colorimetric assay (catalog number 1 644 807, Roche Diagnostics). DMEM and DMEM + WST-1 were included as background controls. As shown in Figure 1A and IB, the peptide of SEQ ID NOs: 5 and 47 clearly show a lack of activity, as compared to an antibiotic control.

EXAMPLE 3 - IN VIVO PROTECTION Mice were infected with S. aureus 25923 via intraperitoneal (IP) injection. Four hours later, the peptides of SEQ ID NOs: 1, 4, 5, 6, 45 and 47 were administered at 12 mg / kg and 24 mg / kg for SEQ. ID. DO NOT. 1 (FIG 2A and 2B), 9.6 mg / kg for SEQ. ID. DO NOT. 5 (FIG 2C), 13 mg / kg for SEQ. ID. DO NOT. 47 (FIG 2D), 12 mg / kg for SEQ. ID. NO, 4 (FIG.2E), 9 mg / kg for SEQ. ID. DO NOT. 6 (FIG.2F), and 13 mg / kg for SEQ. ID. DO NOT. 45 (FIG.2G), via IP injection. Twenty-four hours after infection, the surviving animals were sacrificed, and the intraperitoneal lavage fluid was plated to determine the residual bacterial counts (# of colony forming units per my (CFU / ml)) in the presence and absence of the treatment. with peptide.

The dead animals were assigned with the highest bacterial count of any animal in the study. The peptide of SEQ ID NOs: 1, 4, 5, 6, 45, and 47 clearly showed the protection, as compared to the control, as shown in Figure 2A-2G.

EXAMPLE 4 - IN VIVO PROPHYLATIC PROTECTION Twenty-four hours before infection, the peptide was administered at 12 mg / kg (SEQ ID NO: 1, FIG 3A) and 11.5 mg / kg (SEQ ID No. 5, FIG 3B), via IP injection. The mice were then infected with S. aureus 25923 via IP injection. Twenty-four hours after infection, the surviving animals were sacrificed and the intraperitoneal lavage fluid was plated to determine residual bacterial counts (# of colony forming units per ml (CFU / ml)) in the presence and absence of peptide treatment . The dead animals were assigned with the highest bacterial count of any animal in the study. The peptides of SEQ ID NOs: 1 and 5 clearly demonstrated protection ((0 killed mice (treatment with peptide) versus 2 killed mice (control)) Please see Figures 3A and 5B The results discussed below are obtained by the inventors in connection with the experiments of the Examples 1-4. The inventors have shown that a peptide having the amino acid sequence of those shown in TABLE 1 or as described herein as part of the invention, can increase innate immunity. Specifically, the peptides of SEQ ID NOs: 1, 4, 5, 6, 45, and 47 had the ability to prevent and protect against infection, as demonstrated in the in vivo models (Figures 2A-2G and Example 3; Figures 3A-3B and Example 4). However, the peptide of SEQ ID NOs: 5 and 47 lacked antimicrobial activity, as shown in Example 1 and in Figures 1A-1B. Accordingly, the modulation of innate immunity, via the peptide of SEQ ID NOs: 5 and / or 47, indicates that these peptides can be used as a therapeutic agent for the treatment of infectious disease.

EXAMPLE 5 - PLASMA ACTIVITY ASSAY OF DPPIV WITH MOUSE BLOOD Mouse blood was obtained by cardiac puncture of ICR mice and collected in heparinized blood collection tubes. The blood from several mice was combined and distributed in 300 μ aliquots. The peptide was dissolved in acetate buffered saline, pH 5.5, to a concentration of 9 mM. This Backup solution was added 30 μ? at 300 μ? of blood and mixed by resuspension (blood concentration 0.82 mM). For the control, 30 μ? of the buffered saline solution with acetate, white, was added at 300 μ? of blood. Each group of peptides was prepared in triplicate, while the control was prepared in six replicates. The samples were incubated at 37 ° C in closed microtubes for two hours. After incubation the plasma was isolated from the samples by centrifugation at 4000 rcf. The plasma was transferred to a 96-well assay plate for the DPPIV assay. The assay was initiated by the addition of 5 μ? of the DPPIV substrate, gli-pro-p-nitranilide (16 mM in deionized water) to 95 μ? of plasma (concentration in plasma 0.8 mM) and the increase in UV compliance (405 nm) was monitored in a period of 20 minutes. The rate of production of p-nitroaniline by the enzymatic cleavage of gli-pro-p-nitroaniline was taken as the activity of DPPIV (Durinx C et al., (2001) "Reference valúes for plasma dipeptidyl-peptidase IV activity and their association with other laboratory parameters. "Clin Chem Lab Med. 39 (2): 155-9.) The results can be observed in TABLE 1. The effect of the peptides on DPPIV activity was observed. The results are presented as the percentage activity averaged, normalized in relation to the control saline (adjusted to 100%). Anything less than 100% activity represents a reduction in DPPIV activity. In one aspect of the invention, a reduction in DPPIV activity by about, or in one embodiment, at least 2 %% (for example to about 75%) was considered active. A person skilled in the art would appreciate that the desired level of activity may vary depending on the use of the peptides.

Discussion The serine dipept idyl-peptidase protease IV ransmembranal type II protease (DPPIV), also known as CD26 or the adenosine deaminase binding protein, is a major regulator of various physiological processes including immune functions. CD26 / DPPIV is a glucoprotein of the cell surface of 100 kD that is mainly expressed as mature thymocytes. Activated T cells, B cells, NK cells, macrophages and epithelial cells. It also has two functions, a function of signal transduction and a proteolytic function (Morimoto C, Schlossman SF, The structure and function of CD26 in The T-cell Immune Response, 1998, 161: 55 -70.). One of its cellular roles involves the modulation of the activity of chemokine by cleaving the dipeptides from the N-terminus of the chemokine. The modulation of the NH2 ends of the chemokines is of great importance not only for the binding of their receptors and the following reactions, but also for altering the specificity of the chemokine receptor processed. In addition, it was shown that soluble rCD26 increases transendothelial migration of T cells while reducing the migratory response of monocytes [Oravecz, T. et. al., (1997) Regulation of the receptor specificity and formation of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptydyl peptidase IV (CD26) -media t ed cleavage. J. Exp. Med. 186: 1865-1872; Iwata, S., et. al., (1999) CD26 / dipeptidyl peptidase IV diffrently regulates the chemotaxis of T cells and monocytes to RANTES: possible mechanism for the switch from innate to acquiring immune response. Int. Immunol. 11: 417-426]. These results indicate that CD26 / DPPIV differentially regulate the chemotactic response of T cells and monocytes, and is involved in the change of the acquired innate immune response. As such, a reduction in DPPIV activity could then have the opposite effect, promoting an innate immune response and migratory responses from macrophages It has also been reported that pharmacological inhibition of the enzymatic activity of DPPIV could reduce the progression of arthritis in an experimental rat model of RA (Tanaka S et al., Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225, Immunopharmacology 1998, 40: 21-26; Tanaka S, et al.,: Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV, Int J Immunopharmacol 1997, 19: 15-24), suggesting that decreases in DPPIV activity can relieve inflammation under some circumstances. Together, the anti-inflammatory role and its modulation of chemokine activity make DPPIV a good molecule for the selection of new compounds for these activities. CD26 / DPPIV is involved in the pathology of a variety of diseases, such as the progression of AIDS and HIV disease (Blazquez et al., 1992, Vanham et al., 1993, Schols et al., 1998 Oravecz et al., 1995), Graves diseases (Eguchi et al., 1989; Nishikawa et al., 1995), and cancer (Stecca et al., 1997) and diabetes (Hinke et al 2000, arguet et al., 2000). In addition, CD26 as an indicator of T cell activation has been shown to fluctuate in parallel with several autoimmune diseases such as arthritis rheumatoid (Nakao et al., 1989) and autoimmune thyroiditis (Eguchi et al., 1989). CD26 has been described as a marker that correlates well with the level of activity of these diseases. It has also been studied as an indicator of the progression of the disease in chronic progressive multiple sclerosis (Cons tant inescu et al., 1995). The peptides of the present invention have been shown to reduce the activity of DPPIV. As such, they can be used in the treatment of certain immunological conditions, such as conditions related or associated with DPPIV, and can, in a modular aspect, immunity and inflammation, such as the inflammation that leads to sepsis. While the above invention has been described in some detail for purposes of clarity and understanding, it may be appreciated by a person skilled in the art from a reading of the description, that various changes in form and detail may be made without depart from the true scope of the invention in the appended claims.

TABLE 1 All C-terminally amidated, unless otherwise indicated **** TABLE 1 All C-terminally amidated, unless otherwise indicated **** **% activity of DPPIV (saline, where the control is 100% activity (saline or vehicles alone without the peptide) .Approximately 75% or less activity in relation to the saline control, is desirable. **** OH indicates the Peptide-free acid form Ac indicates acetylated O indicates ornithine, Cit indicates Citrulline, x indicates NMe backbone (versus the amide backbone).

TABLE 1 CONTINUATION Note 1 of Table 1: Xi is selected from the group consisting of K, H, R, S, T, O, Cit, Hci, Dab, Dpr, or glycine-based compounds with basic functional groups substituted on the end N (eg, Nlys), hSer, Val (betaOH) X2 is selected from the group consisting of V, I, K, P, and H including an isolated peptide of up to 10 amino acids comprising an amino acid sequence of the SEQ ID NO: 55 Note 2 of Table 1: wherein Xi is selected from the group consisting of K, H, R, S, T, O, Cit, Hci, Dab, Dpr, or glycine-based compounds with basic functional groups substituted at the extreme N (for example, Nlys), hSer, Val (betaOH) and wherein X2 is selected from the group consisting of A, I, L, V, K, P, G, H, R, S, O, Dab, Dpr, Cit, Hci, Abu, Nva, NIe and where X2 can be N-methylated, and wherein X3 is selected from the group consisting of I, V, P, wherein in a , X3 is not N-methylated. In one embodiment, the isolated peptide may be an amino acid sequence of up to 10 amino acids, but it is not SEQ. ID. NOs 2 or 17.

Note 3 of Table 1: where Xi, X2 and X3 are as defined in Seq. ID. DO NOT. 56, and where "a" is selected from the group consisting of S, P, I, R, C, T, L, V, A, G, K, H, R, O, C, M, and F or an isolated peptide of up to 10 amino acids comprising said sequences.

Note 4 of Table 1: where ??? 2? 3? they are as defined in the SEQ. ID. DO NOT. 56 and "b" is selected from the group consisting of A, A *, G, S, L, F, K, C, I, V, T, Y, R, H, O, and M, but in one embodiment is not P. In one embodiment, the isolated peptide is a peptide of up to 10 amino acids comprising SEQ. ID. DO NOT. 58 but not the SEQ. ID. DO NOT. 17 Note 5 of Table 1: where Xlr X2 and X3 are as defined in SEQ. ID. DO NOT. 56 and "ai" is selected from the group consisting of K, I R, H, O, L, V, A, and G and "a2" is selected from the group consisting of S, P, RT, H, K, 0, L, V, A, G, S, and I. In one embodiment, "ai" does not is acetylated, or where ai is K, K is not acetylated or is not SEQ. ID. DO NOT. 2. In one embodiment, the isolated peptide comprises up to 10 amino acids comprising SEQ. ID. DO NOT. 59 Note 6 of Table 1: where Xi, X2 and X3 are as defined in SEQ. ID. DO NOT. 56 and where "a" is selected from the group consisting of S, R, K, H, O, T, I, L, V, A, and G and wherein "b" is selected from the group consisting of A, V, I, L, G, K, H, R, 0, S, T, and F or a peptide of up to 10 amino acids comprising SEQ. ID. DO NOT. 60 REFERENCES CITED Blazquez MV, Madueno JA, González R, Jurado R, Bachovchin WW, Pena J, Muñoz E.Selective decrease of CD26 expression in T cells from HIV-I -infected individuáis. J Immunol. 1992 Nov 1; 149 (9): 3073-7.

Vanham G, Kestens L, De Meester I, Vingerhoets J, Penne G, Vanhoof G, Scharpe S, Heyligen H, Bosmans E, Ceuppens JL, et al. Decreased expression of the memory marker CD26 on both CD4 + and CD8 + T lymphocytes of HIV-infected subjects. JAcquir Immune Deflc Syndr. 1993 Jul; 6 (7): 7 9-57.

Schols D, Proost P, Struyf S, Uyts A, De Meester I, Scharpe S, Van Damme J, De Clercq E. CD26-RANTES (3-68), but not intact RANTES, has potent anti-HIV-I activity . Antiviral Res. 1998 Oct; 39 (3): 175-87. Erratum in: Antiviral Res 1999 Jan; 40 (3): 189-90.

Oravecz T, Roderiquez G, Koffi J, ang J, Ditto M, Bou-Habib DC, Lusso P, Norcross MA. CD26 expression correlates with entry, replication and cytopathicity of monocytotropic HIV-I strains in a T-cell line. Nat Med. 1995 Sep; 1 (9): 919-26. Comment in: Nat Med. 1995 Sep; 1 (9): 881-2.

Nishikawa Y, Nakamura M, Fukumoto K, Matsumoto M, Matsuda T, Tanaka Y, Yoshihara H. [Adenosine deaminase isoenzymes in patients with Graves' disease] Rinsho Byori. 1995 Oct; 43 (10): 1057-60. [Article in Japanese] Eguchi K, Ueki Y, Shimomura C, Otsubo T, Nakao H, Migita K, Kawakami A, Matsunaga M, Tezuka H, Ishikawa N, et al. Increment in the Tal + cells in the blood and thyroid tissue of patients with Graves' disease. J Immunol. 1989 Jun 15; 142 (12): 4233-40.

Stecca BA, Nardo B, Chieco P, Mazziotti A5 Bolondi L, Cavallari A. Aberrant dipeptidyl peptidase IV (DPP IV / CD2 6) expression in human hepatocellular carcinoma. J Hepatol. 1997Aug; 27 (2): 337-45.

Hinke SA, Pospisilik JA, Demuth HU, Mannhart S, Kuhn-Wache K, Hoffmann T, Nishimura E, Pederson RA, Mclntosh CH. Dipeptidyl peptidase IV (DPIV / CD26) degradation of glucagon. Characterization of glucagon degradation products and DPIV-resistant analogs. J Biol Chem. 2000 Feb 11; 275 (6): 3827-3.

Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, Ribel U, Atanabe T, Drucker DJ, Wagtmann N. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Nati Acad Sci USA. 2000 Jun 6; 97 (12): 6874-9.

Nakao H, Eguchi K, Kawakami A, Migita K, Otsubo T, Ueki Y, Shimomura C, Tezuka H, Matsunaga M, Maeda K, et al. Increase of Such positive cells in blood from patients with rheumatoid arthritis. J Rheumatol. 1989 Jul; 16 (7): 904-10.

Constantinescu CS, Kamoun M, Dotti M, Farber RE, Galetta SL, Rostami A. A longitudinal study of the T cell activation marker CD26 in chronic progressive multiple sclerosis. J Neurol Sci. 1995 Jun; 130 (2): 178 It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (35)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. An isolated peptide, characterized in that it comprises the amino acid sequences of TABLE 1 or an analogue, derivative or variant thereof.
2. 2. The isolated peptide according to claim 1, characterized in that it has a modified C-terminus and / or a modified N-terminus.
3. 3. The isolated peptide according to claim 2, characterized in that it has a modified C-terminus.
4. 4. The isolated peptide according to claim 3, characterized in that it has an amidated C-terminus.
5. 5. The isolated peptide according to claim 1, characterized in that it comprises the amino acid sequence of TABLE 1 as modified by at least one substitution of a D-amino acid.
6. 6. An agent, characterized in that it is reactive with the peptide according to claim 1.
7. 7. The agent according to claim 6, characterized in that it is an antibody.
8. 8. The agent in accordance with the claim 7, characterized in that it is a monoclonal antibody.
9. 9. An isolated nucleic acid molecule, characterized in that it encodes the peptide according to claim 1.
10. 10. A recombinant nucleic acid construct, characterized in that it comprises the nucleic acid molecule according to claim 9 operably linked to a vector expression.
11. 11. At least one host cell, characterized in that it comprises the recombinant nucleic acid construct according to claim 10.
12. 12. A method for producing a peptide comprising an amino acid sequence listed in TABLE 1 or an analog, derivative or variant thereof, characterized in that it comprises the steps of: (a) cultivating at least one host cell according to claim 11, under conditions that allow the expression of the peptide; and (b) recovering the peptide from at least one host cell or culture medium thereof.
13. 13. A pharmaceutical composition, characterized in that it comprises the peptide according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
14. 14. A method to treat and / or prevent infection in a subject, characterized in that it comprises administering to the subject a peptide that includes an amino acid sequence listed in TABLE 1 or an analogue, derivative or variant thereof.
15. 15. The method of compliance with the claim 14, characterized in that the peptide has the amino acid sequence of SEQ ID NOs: 1, 3-16, 18-60.
16. 16. The method according to claim 14, characterized in that the peptide modulates the innate immunity in the subject, thereby treating and / or preventing infection in the subject.
17. 17. The method according to claim 14, characterized in that the infection is a microbial infection.
18. 18. The method of compliance with the claim 17, characterized in that the infection is selected from the group consisting of an infection by a bacterium, an infection by a fungus, an infection by a parasite, and an infection by a virus.
19. 19. The method according to the claim 18, characterized in that the bacteria is a Gram-positive or Gram-negative bacteria.
20. 20. The method of compliance with the claim 19, characterized in that the bacterium is selected from the group consisting of E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp, Staphylococcus aureus, Streptococcus spp. , and vancomycin-resistant enterococci.
21. The method according to claim 18, characterized in that the fungus is selected from the group consisting of a mold, a yeast, and a superior fungus.
22. 22. The method according to claim 18, characterized in that the parasite is unicellular or multicellular.
23. 23. The method according to the claim 22, characterized in that the parasite is selected from the group consisting of Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondii.
24. 24. The method according to claim 18, characterized in that the virus is associated with a condition selected from the group consisting of AIDS, avian flu, fowlpox, cold sore, common cold, gastroenteritis, glandular fever, influenza, tract infection lower respiratory tract, measles, mumps, pharyngitis, pneumonia, rubella, SARS and upper respiratory tract infection.
25. 25. The method according to claim 24, characterized in that the virus is the respiratory syncytial virus.
26. 26. The method of compliance with the claim 14, characterized in that the subject has, or is at risk of having an infection.
27. 27. The method according to claim 26, characterized in that the peptide is administered orally, parenterally, transdermally, intranasally, by pulmonary administration or by osmotic pump.
28. 28. A method for predicting whether a subject could respond to treatment for a microbial infection or an immune-related disorder, characterized in that the treatment comprises administering to the subject a peptide comprising an amino acid sequence of TABLE 1 or an analog, derivative or variant thereof, the method comprises evaluating a subject diagnostic sample for DPPIV activity by administering to the sample the peptide of the invention in the presence of a DPPIV substrate under conditions that could allow DPPIV to react with the substrate, wherein the reduction of DPPIV activity in comparison to a control without the peptide, is indicative that the subject could respond to the treatment.
29. 29. An isolated peptide, characterized in that it comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-60.
30. 30. An isolated peptide according to claim 29, characterized in that the amino acid sequence is selected from the group consisting of the SEQ ID NOs: 1, 3-16, 18-60.
31. 31. An isolated peptide according to claim 30, characterized in that the amino acid sequence is selected from the group consisting of SEQ ID NOs: 1, 3-16, 18-54.
32. 32. An isolated peptide according to any of claims 29 or 30, characterized in that it comprises immunological activity.
33. 33. An isolated peptide according to claim 32, characterized in that it consists of up to 10 amino acids.
34. 34. The use of an isolated peptide according to any of claims 32 or 33, in the treatment of an infection related to DPPIV.
35. 35. The use of a peptide according to any of claims 32 or 33, for the treatment of an infection or an innate condition related to the immune system.