WO2017074118A1 - Composition pharmaceutique contenant des cellules dendritiques exprimant foxp3 pour réguler l'immunité - Google Patents

Composition pharmaceutique contenant des cellules dendritiques exprimant foxp3 pour réguler l'immunité Download PDF

Info

Publication number
WO2017074118A1
WO2017074118A1 PCT/KR2016/012289 KR2016012289W WO2017074118A1 WO 2017074118 A1 WO2017074118 A1 WO 2017074118A1 KR 2016012289 W KR2016012289 W KR 2016012289W WO 2017074118 A1 WO2017074118 A1 WO 2017074118A1
Authority
WO
WIPO (PCT)
Prior art keywords
cells
foxp3
fxdc
present
blood
Prior art date
Application number
PCT/KR2016/012289
Other languages
English (en)
Korean (ko)
Inventor
배용수
정이들
강명호
변세은
Original Assignee
성균관대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 성균관대학교산학협력단 filed Critical 성균관대학교산학협력단
Publication of WO2017074118A1 publication Critical patent/WO2017074118A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4615—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells

Definitions

  • the present invention relates to a pharmaceutical composition for immunomodulation, More specifically, the present invention relates to a pharmaceutical composition for immunomodulation comprising dendritic cells expressing Foxp3.
  • the immune system consists of immune tolerance, which is a mechanism for suppressing and regulating immunity, and an immune response that promotes immunity.
  • the immune system maintains immune homeostasis by properly balancing these two immune actions. have. This maintained immunological balance can lead to imbalances for a variety of causes, which eventually lead to various diseases. Immunological imbalance can result if the immune tolerant function is stronger than the immune response or vice versa. For example, when immune tolerance is stronger than that of the immune response, the human immune system may easily develop cancer, invade foreign viruses, and pathogenic bacteria, and may cause cancer or viral and bacterial diseases.
  • Immunosuppressants refer to a variety of substances that are used to reduce or block the host's ability to produce antibodies (humidary immune response) or cellular immune response to the action of an antigen.
  • it is also usefully used for skin hypersensitivity reactions, such as autoimmune diseases such as lupus, rheumatoid arthritis, atopy, allergy (see Korean Patent Publication No. 10-2015-0026839).
  • immunosuppressive agents such as cyclosporin A and FK506 are compounds derived from natural products having a complicated chemical structure and are expensive in terms of supply and demand of raw materials, and thus are inexpensive and carry a risk that various side effects may be caused by long-term administration. Therefore, there is an urgent need for the development of new immunomodulators that exhibit low toxicity and are capable of economic production.
  • dendritic cells (Dendritic Cell, DC) has a variety of characteristics depending on the origin, form, phenotype, function, maturation process, etc., in particular, can promote or inhibit the T cell response depending on the situation, the homeostasis of the immune system Plays an important role in regulating
  • the basic study of conventional dendritic cells was performed by using bone marrow-derived dendritic cells (BMDC) made by artificially differentiating mouse bone marrow cells or by separating DCs residing in secondary lymphoid tissues such as mouse spleen and lymph nodes.
  • BMDC bone marrow-derived dendritic cells
  • secondary lymphoid tissues such as mouse spleen and lymph nodes.
  • the present inventors have found for the first time the dendritic cells expressing Foxp3 present only in the blood, and tried to provide the basic data for the development of disease treatments according to immune imbalance by identifying their immune regulation and immune homeostasis maintenance effect.
  • the present invention has been made to solve the above-mentioned conventional problems, the present inventors have confirmed the immune homeostasis maintenance effect of the dendritic cells expressing Foxp3 present in the blood, and completed the present invention based on this.
  • an object of the present invention is to provide a pharmaceutical composition for immunomodulation comprising dendritic cells expressing Foxp3 as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, including dendritic cells expressing Foxp3 as an active ingredient.
  • Another object of the present invention is to isolate the myeloid-derived suppressor cells (MDSC) present in the blood; And culturing the isolated bone marrow-derived suppressor cells in a medium containing granulocyte-macrophage colony-stimulating factor (GM-CSF).
  • MDSC myeloid-derived suppressor cells
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • the present invention provides a pharmaceutical composition for immunomodulation, comprising dendritic cells expressing Foxp3 as an active ingredient.
  • Foxp3 may be composed of the amino acid sequence set forth in SEQ ID NO: 1.
  • the dendritic cells may be isolated from blood.
  • the composition can modulate immune homeostasis in the blood.
  • the composition can propagate CD8 + regulatory T cells (CD8 + Tregs).
  • the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, including dendritic cells expressing Foxp3 as an active ingredient.
  • the present invention comprises the steps of separating the myeloid-derived suppressor cells (MDSC) present in the blood; And it provides a method for producing dendritic cells expressing Foxp3 comprising the step of culturing the isolated bone marrow-derived suppressor cells in a medium containing GM-CSF.
  • MDSC myeloid-derived suppressor cells
  • the myeloid-derived suppressor cells may be monocytic myeloid-derived suppressor cells (M-MDSC).
  • the present invention provides a method for treating an inflammatory disease comprising administering the pharmaceutical composition to a subject.
  • the present invention provides a novel use of dendritic cells expressing Foxp3 for the preparation of a therapeutic agent for an inflammatory disease.
  • the composition according to the present invention comprises a dendritic cell (fxDC) expressing Foxp3 as an active ingredient
  • fxDC dendritic cell
  • the fxDC is a key immune cell involved in the immune homeostasis of the blood itself, the number of individuals in an imbalanced state such as an infectious disease It is possible to strongly inhibit the proliferation of effector T cells in the blood through the regulation of CD8 + regulatory T cell (CD8 + Treg) proliferation, which is useful as a pharmaceutical composition for the prevention or treatment of chronic inflammatory immune diseases. It is expected to be able to be used.
  • the reduction of CD8 + Treg cells is one of the characteristics of immune senescence, and in the elderly, the CD8 + Treg cells decrease the immune homeostasis and increase the number of patients with chronic inflammatory diseases or autoimmune diseases. No cause of decline was found.
  • fxDC in the blood is a causative immune cell that induces the proliferation of CD8 + Tregs.
  • dendritic cells expressing Foxp3 can be used as a pharmaceutical composition for the treatment of immune aging.
  • Figure 2a is the result of re-analysis by reverse gating the presence of fxDC with a T cell marker (CD3) in mouse peripheral blood mononuclear cells (mPBMC).
  • CD3 T cell marker
  • Figure 2b is a result confirming that fxDC is not pDC using plasmacytoid DC (pDC) specific surface antigen (CD11c, and B220).
  • pDC plasmacytoid DC
  • Figure 2c is a result of investigating the expression of Macrophage (macrophage) specific surface antigens (CD11b, CD14, F4 / 80 and CD64) in fxDC present in peripheral blood to confirm that fxDC is not monocytes or macrophages.
  • Macrophage macrophage
  • CD11b, CD14, F4 / 80 and CD64 specific surface antigens
  • Figure 3 shows the results of the change in the presence and population of fxDC in the normal and acute (LCMV armstrong) and chronic (LCML clone13) virus infected mouse blood.
  • Figure 4 shows the results confirmed by FACS after analyzing the mobility of the fxDC CCL19 by transwell experiments.
  • 5 is a result of dividing mPBMC into CD11c + cell group and CD11c- cell group in order to identify progenitor cells of fxDC, and confirming the differentiation into fxDC in each group.
  • Figure 6 shows the results of FACS analysis of differentiation of fxDC after culturing MDSCs subgroups (DP-MDSC, G-MDSC, M-MDSC, and DN cells) in the presence of GM-CSF for 3 days.
  • T cells 7 is a result of co-culture of CFSF-labeled syngeneic T cells with mDC, G-MDSC, M-MDSC, DP-MDSC, and fxDC for 3 days to confirm the proliferation of T cells.
  • FIG. 8 shows CD4 + regulatory T cells that are generated when Foxp3-GFP mouse T cells are treated with CD3 and CD28 antibodies and co-cultured with mDC, G-MDSS, M-MDSC, DP-MDSC, or fxDC. (CD4 + Tregs) and CD8 + regulatory T cells (CD8 + Tregs).
  • FIG. 9 shows the inhibition of proliferation of CD8 + T cells of fxDC by fxDC and coculture with fxDC and coculture with a transwell plate (cell binding block) after activation and activation of CD3 and CD28 antibodies to normal mouse T cells. The results were confirmed to be due to direct contact and not by cain.
  • FIG. 10 shows CD4 + regulatory T cells generated when Foxp3-GFP mouse T cells are treated with CD3 and CD28 antibodies and then co-cultured with mDC, G-MDSS, M-MDSC, DP-MDSC, or fxDC. (CD4 + Tregs) and CD8 + regulatory T cells (CD8 + Tregs).
  • fxDC Foxp3 + dendritic cells
  • MDSC bone marrow-derived suppressor cells
  • the fxDCs were differentiated from the cells (M-MDSCs).
  • blood fxDC unlike other immunoregulatory DCs, confirms the novel fact that it induces proliferation of CD8 + regulatory T cells (CD8 + Tregs) rather than CD4 + regulatory T cells (CD4 + Tregs) to regulate T cell activity and completes the present invention It was.
  • the present invention provides a pharmaceutical composition for immunomodulation comprising dendritic cells expressing Foxp3 as an active ingredient.
  • the Foxp3 protein preferably has an amino acid sequence as set forth in SEQ ID NO: 1, but is not limited thereto, and 70% or more, preferably 80% or more, more preferably 90% or more, and most preferably 70% or more of the amino acid sequence. May comprise a protein represented by an amino acid sequence having at least 95% homology.
  • dendritic cells (Dendritic Cells, DC) is one of the important antigen presenting cells (APC) that initiates an antigen specific adaptive immune response, which may be derived from human or mouse, preferably dendritic from human blood Cells may be isolated or differentiated from monocytes isolated from blood into dendritic cells, but are not limited thereto.
  • APC antigen presenting cells
  • dendritic cells (fxDC) expressing Foxp3 are essential immune cells involved in the immune homeostasis of the blood itself, and do not exist in a normal state, but are newly generated only in an imbalanced state, thereby generating CD8 + regulatory T cells ( CD8 + Tregs) can be strongly inhibited the proliferation of effector T cells in the blood through the regulation of proliferation, it is expected to be useful as a pharmaceutical composition for the prevention or treatment of inflammatory diseases.
  • CD8 Tregs are induced, CD4 Tregs are not induced, and CD8 T cell activity is specifically inhibited, which is different from the existing recombinant FoxP3 expressing dendritic cells.
  • the recombinant Foxp3 expressing dendritic cells treated with the anti-TGF- ⁇ antibody disappeared the immunosuppressive activity, and showed immunosuppressive activity by cytokines, but Foxp3 expressing dendritic cells in the body or prepared through in vitro differentiation.
  • Dendritic cells were found to be different from recombinant dendritic cells because they exhibited the property of inhibiting T cell immunity by direct contact rather than indirect immune suppression by cytokines.
  • the term "immunoregulation" used in the present invention means to alleviate immune imbalance in the blood and maintain immune homeostasis. Maintaining immune homeostasis refers to a condition in which a balance between immune tolerance and immune response-immunity-promoting mechanisms is maintained. Is an essential element.
  • the present invention is the first to reveal that when the imbalance in the blood caused fxDC present in the blood increases, they induce CD8 + regulatory T cells (CD8 + Tregs) proliferation, maintaining immune homeostasis in the blood There is a characteristic.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, including dendritic cells expressing Foxp3 as an active ingredient.
  • prevention means any action that inhibits or delays the development of an inflammatory disease by administration of a pharmaceutical composition according to the present invention.
  • treatment means any action in which symptoms for inflammatory diseases are improved or beneficially altered by administration of the pharmaceutical composition according to the invention.
  • CD11c + Foxp3 + dendritic cells fxDC
  • various lymphoid organs Spleen, inguinal lymph node, mesenteric lymph node, peyer's patch and thymus, Lung, Bone marrow
  • Foxp3 was highly expressed in regulatory T cells (Treg cells) of lymphoid organs or tissues, whereas Foxp3 was not expressed in immune cells isolated from lymphoid organs (see Example 1).
  • monocyte-derived myeloid-derived suppressor cells M-MDSCs
  • fxDC monocyte-derived myeloid-derived suppressor cells
  • CD8 + regulatory T cells CD8 + Tregs
  • the dendritic cells expressing Foxp3 may be used as an active ingredient of a pharmaceutical composition for regulating cellular immune and / or preventing or treating inflammatory diseases. Suggests that it can (see Example 6).
  • composition of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. It may also be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories, and sterile injectable solutions according to conventional methods.
  • Carriers, excipients and diluents which may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts.
  • the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general It may be administered in an amount of 0.1 mg / kg to 100 mg / kg, preferably in an amount of 1 to 30 mg / kg per day, it may be administered once or several times a day.
  • the pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be expected, for example, by subcutaneous, intravenous, intramuscular or intrauterine dural or cerebrovascular injections.
  • the pharmaceutical composition of the present invention is determined according to the type of drug that is the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient and the severity of the disease.
  • the invention provides a method of treating an inflammatory disease comprising administering the pharmaceutical composition to a subject.
  • subject means a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses and cattle, etc. Mean mammal.
  • the present invention comprises the steps of separating the myeloid-derived suppressor cells (MDSC) present in the blood; And culturing the isolated bone marrow-derived suppressor cells in a medium containing granulocyte-macrophage colony-stimulating factor (GM-CSF). to provide.
  • MDSC myeloid-derived suppressor cells
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • CD11c + Foxp3 + dendritic cells in various lymphoid organs and mucosal tissues (Spleen, inguinal lymph node, mesenteric lymph node, peyer's patch, thymus, lung, bone marrow) in the mouse were analyzed by FACS (Fluorescence activated cell sorter). .
  • Foxp3 was highly expressed in regulatory T cells of lymphoid organs or tissues, whereas Foxp3 was not expressed in immune cells isolated from lymphoid organs.
  • Foxp3 was reported to be expressed only in CD4 + regulatory T cells, and reanalysis by CD3 reverse gating confirmed that Foxp3 + expressing dendritic cells were not caused by contamination of Foxp3 + regulatory T cells (FIG. 2A).
  • Dendritic cells present in the blood are composed of plasmacytoid DC (pDC) directly differentiated from common DC precursor (CDP) and pre-conventional DC (pre-cDC) in the form of progenitor cells.
  • pDC plasmacytoid DC
  • pre-cDC pre-conventional DC
  • dendritic cells in the blood may be either pDCs differentiated directly from CDP, or pre-DCs of differentiation stages.
  • the present inventors examined pDC specific surface antigen expression to determine whether the fxDC is derived from pDC.
  • the cells gated with B220 + did not express GFP (Foxp3) in any case irrespective of the expression of CD11c, and even when gated with CD11c, B220 + cells expressed GFP (Foxp3). It was confirmed not to.
  • macrophages have M1, M2, and TAM (Tumor associated macrophage) that induce or inhibit immunity to the same antigen presenting cells as dendritic cells.
  • TAM Tumor associated macrophage
  • dendritic cells (Foxp3 + dendritic cells) expressing Foxp3 were named fxDC.
  • Blood cDCs are activated by capturing and breaking down invading pathogens or foreign antigens, and migrate to the spleen or local lymph nodes to deliver antigens to T cells, thereby activating acquired immunity.
  • the present inventors expect fxDC to play an important role in intractable immune disease, and therefore, fxDC in the blood of acute infection model (LCMV Arm), and chronic infection model (LCMV C13) using lymphocytic chriomeningitis virus (LCMV). Population changes were investigated.
  • fxDC Foxp3 + dendritic cells
  • PBMC peripheral blood mononuclear cells
  • CD11c bead were filled in the upper chambers of a 24-well transwell plate (8 ⁇ M pore size polycarbonate filter, Corning Costar, Cambridge, Mass.) And 0.6 ml in the lower chambers.
  • PBMC peripheral blood mononuclear cells
  • the trans well plate was left in a CO 2 incubator at 37 ° C. for 3 hours. Foxp3 + cells (Foxp3-GFP) migrated to the upper chamber and the lower chamber were analyzed by FACS.
  • Example 2 it was confirmed that the fxDC of the present invention was not derived from plasmacytoid DC (pDC), and it was intended to confirm whether it is derived from CD11c + pre-conventional DC (pre-cDC). Specifically, mouse blood PBMCs were divided into CD11c + cells and CD11c ⁇ cells, followed by further differentiation with GM-CSF for one day, and the expression of each Foxp3 (GFP) was examined.
  • pDC plasmacytoid DC
  • pre-cDC pre-conventional DC
  • the fxDC of the present invention is not derived from pre-cDC, that is, DC precursor cells, but differentiated into CD11c + fxDC in CD11c (-) precursor cells. In other words, fxDC progenitor cells are present in the CD11c- cell population.
  • the present inventors confirmed that the fxDC population increased significantly in the blood of the existing tumor model, and fxDC was not derived from the existing dendritic cell progenitor cells (pre-cDC) through the above experiments.
  • Myeloid derived suppressor cells (MDSCs), on the other hand, have two main subtypes: CD11b + Ly6G + Ly6C low granulocytic MDSCs (G-MDSCs), and mononuclear myeloid suppressor cells (MDSCs).
  • M-MDSCs CD11b + Ly6G - Ly6C high monocytic MDSCs
  • TAM tumor-associated macrophage
  • GM-CSF dendritic cells involved in immunity by GM-CSF
  • GM-CSF treatment is an essential factor in the differentiation of DCs from blood progenitor cells
  • dendritic cells in GM-CSF medium for 3 days were treated with MDSCs subgroups (DP-MDSC, G-MDSC, M-MSDC, DN cells) isolated from blood. After differentiation, the expression of Foxp3 (GFP) in subdivision differentiated cells was examined. In addition, MDSCs subgroups were labeled with CFSF prior to the incubation process, and FACS was confirmed for cell proliferation during differentiation.
  • MDSCs subgroups DP-MDSC, G-MDSC, M-MSDC, DN cells
  • fxDC of the present invention was differentiated into fxDC by GM-CSF secreted in an inflammatory environment, a part of M-MDSC present in a large amount in blood.
  • T cell proliferation was confirmed by co-culture of fxDC differentiated from T cells and M-MDSC.
  • CD4 + Tregs CD4 + regulatory T cells
  • CD8 + Tregs CD8 + regulatory T cells
  • M-MDSC a precursor of G-MDSC or fxDC
  • mDC mature BMDC
  • DP-MDSC or fxDC Confirmed little induction of T cell proliferation
  • T cells activated / proliferated by CD3 / CD28 were co-cultured with fxDC
  • CD4 + T cell proliferation was not inhibited at all, whereas only CD8 + T cells selectively inhibited proliferation, and Foxp3 / DTR mice were suppressed.
  • fxDC was removed from blood DC, it was confirmed that the proliferation of CD8 + T cells was recovered (FIG. 8).
  • fxDC directly contacts T cells to regulate T cell immunity (FIG. 9).
  • MDSC subgroups induce CD4 + regulatory T cell (CD4 + Tregs) proliferation to regulate T cell activity, whereas fxDC significantly increases CD8 + regulatory T cell (CD8 + Tregs) population and CD4 + regulatory T (CD4 + Tregs) at all. It was confirmed that no adjustment was made (FIG. 10).
  • fxDC strongly regulates the proliferative activity of CD8 + effector T cells (CTL) antigen-specifically through the proliferation of CD8 + Tregs.
  • the composition according to the present invention comprises a dendritic cell (fxDC) expressing Foxp3 as an active ingredient
  • fxDC dendritic cell
  • the fxDC is a key immune cell involved in the immune homeostasis of the blood itself, the number of individuals in an imbalanced state such as an infectious disease It is possible to strongly inhibit the proliferation of effector T cells in the blood through the regulation of CD8 + regulatory T cell (CD8 + Treg) proliferation, which is useful as a pharmaceutical composition for the prevention or treatment of chronic inflammatory immune diseases. It is expected to be able to be used.
  • the reduction of CD8 + Treg cells is one of the characteristics of immune senescence, and in the elderly, the CD8 + Treg cells decrease the immune homeostasis and increase the number of patients with chronic inflammatory diseases or autoimmune diseases. No cause of decline was found.
  • fxDC in the blood is a causative immune cell that induces the proliferation of CD8 + Tregs.
  • dendritic cells expressing Foxp3 can be used as a pharmaceutical composition for the treatment of immune aging.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne une composition pharmaceutique contenant des cellules dendritiques exprimant Foxp3 pour réguler l'immunité. La présente invention a permis de confirmer l'efficacité, dans un état de déséquilibre immunitaire, de l'utilisation de cellules dendritiques Foxp3+ présentes uniquement dans le sang afin d'inhiber la prolifération de lymphocytes T, et de restaurer et maintenir l'homéostasie immunologique par l'activation de lymphocytes T régulateurs des CD8+ (Tregs CD8+), et, en tant que telle, la présente invention est susceptible de permettre un traitement ciblé, quant à la prévention et au traitement de troubles immunitaires, au moyen d'une approche plus fondamentale.
PCT/KR2016/012289 2015-10-29 2016-10-28 Composition pharmaceutique contenant des cellules dendritiques exprimant foxp3 pour réguler l'immunité WO2017074118A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020150150688A KR101734697B1 (ko) 2015-10-29 2015-10-29 Foxp3를 발현하는 수지상 세포를 포함하는 면역 조절용 약학적 조성물
KR10-2015-0150688 2015-10-29

Publications (1)

Publication Number Publication Date
WO2017074118A1 true WO2017074118A1 (fr) 2017-05-04

Family

ID=58630639

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2016/012289 WO2017074118A1 (fr) 2015-10-29 2016-10-28 Composition pharmaceutique contenant des cellules dendritiques exprimant foxp3 pour réguler l'immunité

Country Status (2)

Country Link
KR (1) KR101734697B1 (fr)
WO (1) WO2017074118A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11806364B2 (en) 2017-09-28 2023-11-07 Industry-Academic Cooperation Foundation, Yonsei University Method for producing myeloid-derived suppressor cells, myeloid-derived suppressor cells produced thereby, and methods thereof
KR101944723B1 (ko) * 2017-09-28 2019-02-07 연세대학교 산학협력단 I형 인터페론을 이용한 골수유래 면역반응 억제세포의 제조방법, 이에 의해 제조된 골수유래 면역반응 억제세포 및 그 용도
KR102118116B1 (ko) * 2019-03-20 2020-06-02 충남대학교 산학협력단 Foxp3 또는 이를 코딩하는 유전자를 포함하는 나노입자 및 이의 용도

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150116614A (ko) * 2014-04-08 2015-10-16 성균관대학교산학협력단 Dab2 유전자가 넉 다운된 수지상 세포를 포함하는 암 예방 또는 치료용 약학적 조성물

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150116614A (ko) * 2014-04-08 2015-10-16 성균관대학교산학협력단 Dab2 유전자가 넉 다운된 수지상 세포를 포함하는 암 예방 또는 치료용 약학적 조성물

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE protein [O] 4 June 2017 (2017-06-04), "forkhead box protein P3 [Mus musculus]", XP055380219, retrieved from NCBI Database accession no. np_473380.1 *
GONG, Y. -B. ET AL.: "Effects of Foxp3 Gene Modified Dendritic Cells on Mouse Corneal Allograft Rejection", INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 8, no. 3, March 2015 (2015-03-01), pages 3965 - 3973, XP055380205 *
LIPSCOMB, M. W. ET AL.: "DC Expressing Transgene Foxp3 are Regulatory APC", EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 40, 2010, pages 480 - 493, XP055380202 *
VAN DE LAAR, L. ET AL.: "Regulation of Dendritic Cell Development by GM-CSF: Molecular Control and Implications for Immune Homeostasis and Therapy", BLOOD, vol. 119, no. 15, 2012, pages 3383 - 3393, XP055380210 *

Also Published As

Publication number Publication date
KR101734697B1 (ko) 2017-05-11

Similar Documents

Publication Publication Date Title
WO2017142187A1 (fr) Kit d'addition de milieu pour la culture de cellules nk et procédé de culture de cellules nk (cellules tueuses naturelles) utilisant le kit
WO2010013947A2 (fr) Procédé de développement de cellules tueuses naturelles
WO2017074118A1 (fr) Composition pharmaceutique contenant des cellules dendritiques exprimant foxp3 pour réguler l'immunité
WO2019117633A1 (fr) Composition cosmétique et composition pharmaceutique pour atténuer la dermatite atopique, la chute des cheveux et les plaies ou réduire les rides de la peau
WO2017069512A1 (fr) Procédé d'induction et de prolifération de cellules t spécifiques d'un antigène viral
WO2019124666A2 (fr) Composition pharmaceutique comprenant un inhibiteur de l'interleukine-17 et un inhibiteur du facteur de nécrose tumorale alpha en tant que principes actifs pour la prévention ou le traitement d'une maladie pulmonaire inflammatoire neutrophilique
JP2000509604A (ja) サプレッサー細胞集団を生成するためのインターロイキン―１０の使用
Bissonnette et al. Interferons differentially regulate histamine and TNF-alpha in rat intestinal mucosal mast cells.
WO2022102887A1 (fr) Procédé de culture par prolifération massive de cellules nk
WO2019198995A1 (fr) Procédé de conversion à base d'exosomes pour cellules immunitaires
WO2019103436A9 (fr) Composition pour la culture de cellules nk et procédé pour la culture de cellules nk l'utilisant
Tamesis et al. The role of natural killer cells in the development of herpes simplex virus type 1 induced stromal keratitis in mice
WO2021150078A1 (fr) Cellules immunitaires et cellules souches prêtes à l'emploi, et composition pharmaceutique les comprenant
WO2015199402A1 (fr) Procédé de préparation de cellules dendritiques à expression augmentée d'un gène spécifique, et composition pour le traitement ou la prévention de maladies auto-immunes, contenant des cellules dendritiques préparées à l'aide de celui-ci
US8105601B2 (en) Compositions and methods for modulating an immune response
WO2020122405A1 (fr) Composition pour la prévention ou le traitement de maladies inflammatoires, comprenant des cellules souches mésenchymateuses dérivées de cellules souches dédifférenciées
WO2012050269A1 (fr) Composition comprenant la protéine rv0351 de mycobacterium tuberculosis pour la promotion de la maturation de cellules dendritiques
WO2019168222A1 (fr) Composition de milieu de culture pour la culture de lymphocytes activés anticancereux dérivées de cellules mononucléaires du sang périphérique et procédé de culture de lymphocytes activés anticancereux l'utilisant
WO2015023147A1 (fr) Cellule souche mésenchymateuse traitée par un inhibiteur de signal mtor/stat3 ayant une activité immunomodulatrice, et composition pour thérapie cellulaire la comprenant, destinée à prévenir ou traiter des troubles immuns
WO2021177599A1 (fr) PROCÉDÉ DE PRODUCTION DE CELLULES NK DE TYPE MÉMOIRE PRÉSENTANT UNE APTITUDE À EXPRIMER DES NIVEAUX SUPÉRIEURS DE NCR, DE CYTOTOXICITÉ ET D'IFN-γ PAR RAPPORT À DES CELLULES NK DANS LE SANG PÉRIPHÉRIQUE HUMAIN
WO2022108165A1 (fr) Procédé de production d'exosomes isolés à partir de cellules souches mésenchymateuses dérivées de cellules souches pluripotentes induites, et utilisation associée
KR20170051376A (ko) Foxp3를 발현하는 수지상 세포를 포함하는 면역 조절용 약학적 조성물
WO2021006420A1 (fr) Procédé de régulation de l'apoptose de lymphocytes t par traitement de la phospholipase a2
WO2023204615A1 (fr) Procédé de production de cellules tueuses naturelles de type mémoire et utilisation anticancéreuse de cellules tueuses naturelles de type mémoire ainsi produites
WO2023096352A1 (fr) Lignée de cellules nourricières génétiquement modifiées pour exprimer hla-e et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16860301

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16860301

Country of ref document: EP

Kind code of ref document: A1