WO2015194710A1 - Composition comprenant des cellules souches mésenchymateuses traitées avec un inhibiteur de stat3 en tant que principe actif pour la prévention ou le traitement de maladies immunitaires - Google Patents

Composition comprenant des cellules souches mésenchymateuses traitées avec un inhibiteur de stat3 en tant que principe actif pour la prévention ou le traitement de maladies immunitaires Download PDF

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WO2015194710A1
WO2015194710A1 PCT/KR2014/010021 KR2014010021W WO2015194710A1 WO 2015194710 A1 WO2015194710 A1 WO 2015194710A1 KR 2014010021 W KR2014010021 W KR 2014010021W WO 2015194710 A1 WO2015194710 A1 WO 2015194710A1
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cells
acid
mesenchymal stem
dihydroxy
stem cells
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Korean (ko)
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조미라
박성환
양철우
박민정
윤덕규
김석중
이선영
이은정
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가톨릭대학교 산학협력단
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Priority claimed from KR1020140144100A external-priority patent/KR101705412B1/ko
Publication of WO2015194710A1 publication Critical patent/WO2015194710A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals

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  • the present invention relates to a cell therapy composition for the prevention or treatment of immune diseases, including mesenchymal stem cells treated with STAT3 inhibitors as an active ingredient.
  • a method for treating a disease caused by an excessive immune response is to alleviate or reduce various symptoms caused by the disease by administering an immunosuppressant alone or in combination.
  • Immunosuppressants refer to a variety of substances used to reduce or block the host's ability to produce antibodies (a humoral immune response) or a cellular immune response to the action of an antigen. Such immunosuppressive agents may be useful for autoimmune diseases such as lupus, rheumatoid arthritis, and skin hypersensitivity reactions such as atopy and allergy as well as organ transplant field. A good immunosuppressant should be able to control the imbalance of the immune response, ensure the safety of the human body, and reduce the incidence of disease recurrence during long-term treatment.
  • immunosuppressive agents include cyclosporin A and FK506, which are compounds derived from natural products with complex chemical structures, which are expensive in terms of supply and demand of raw materials, which are uneconomical and may cause various side effects due to long-term administration. There is a risk. Therefore, there is an urgent need for the development of new immunosuppressive agents capable of economic production with low toxicity and induction of immune tolerance.
  • T cells are one of a group of cells that play a central role in the immune system as a biological defense system against various pathogens.
  • T cells are produced in the thymus of the human body and undergo a series of differentiation processes to differentiate into T cells with unique characteristics.
  • T cells which have completed differentiation, are largely divided into type 1 helper cells (Th1) and type 2 according to their function. It is divided into helper cells (Th2).
  • Th1 cells the main function of Th1 cells is involved in cell mediated immunity
  • Th2 cells are involved in humoral immunity
  • these two cell populations are balanced with each other so that they are not activated with each other.
  • immune diseases can be attributed to the imbalance between these two immune cells, for example, when the activity of Th1 cells is abnormally increased, autoimmune diseases may occur, and the activity of Th2 cells is abnormally increased. It is known that immune diseases occur due to hypersensitivity reactions.
  • Tregs immunoregulatory T cells
  • Th17 cells are known to be formed through a process similar to the differentiation of Treg cells during the differentiation of undifferentiated T cells. In other words, differentiation of Treg cells and Th17 cells occurs in the presence of TGF- ⁇ in common, but does not require IL-6 in Treg cells, whereas IL-6 is present in combination with TGF- ⁇ in Th17 cells. Differentiate in situations where In addition, differentiated Th17 cells are characterized by the secretion of IL-17.
  • Th17 cells Unlike Treg cells, Th17 cells have been found to be involved in the forefront of inflammatory reactions seen in immune diseases, maximizing the signal of inflammatory responses and accelerating disease progression. Therefore, in the case of autoimmune diseases which are not controlled by Treg cells among autoimmune diseases, development of therapeutic agents for autoimmune diseases that target the inhibition of Th17 cell activity has been highlighted.
  • immunosuppressive drugs are immunosuppressants that block signal transduction pathways in T cells. These immunosuppressive agents are toxic, infection, lymphoma, diabetes, tremor, headache, diarrhea, high blood pressure, and nausea. There is a problem that side effects such as renal failure occur.
  • an object of the present invention is to provide a cell therapy composition for the prevention or treatment of immune diseases, including mesenchymal stem cells treated with a STAT3 (Signal transducer and activator of transcription 3) inhibitor as an active ingredient.
  • STAT3 Signal transducer and activator of transcription 3
  • STAT3 signal transducer and activator of transcription 3
  • Another object of the present invention is to co-cultivate undifferentiated T cells into Th1 cells and Th17 cells, comprising co-culturing with mesenchymal stem cells treated with a signal transducer and activator of transcription 3 (STAT3) inhibitor. It is to provide a method for inhibiting activity.
  • STAT3 signal transducer and activator of transcription 3
  • Another object of the present invention is co-culture of undifferentiated T cells with mesenchymal stem cells treated with a signal transducer and activator of transcription 3 (STAT3) inhibitor, Regulatory T cells (Treg: Treg) It is to provide a method for promoting differentiation and activity into).
  • STAT3 signal transducer and activator of transcription 3
  • Treg Treg
  • the present invention provides a cell therapy composition for the prevention or treatment of immune diseases comprising mesenchymal stem cells treated with a STAT3 (Signal transducer and activator of transcription 3) inhibitor as an active ingredient.
  • STAT3 Synignal transducer and activator of transcription 3
  • the STAT3 inhibitor is STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 (2H) -trione), AG-490 ((E) -2-Cyano-3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide), Atiprimod; 3- (8,8-dipropyl-3-azaspiro [4.5] decan-3 -yl) -N, N-diethylpropan-1-amine, Auranofin (3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), Aurothiomalate (Sodium) 2- (auriosulfanyl) -3-carboxypropanoate), BMS-354825 (Dasatinib; N- (2-chloro-6-methylphenyl) -2-[[6- [4- (2-)
  • the statin compound is cilastatin (cilastatin), nystatin (nystatin), lovastatin (lovastatin), somatostatin (somatostatin), pravastatin, simvastatin (simvastatin), fluvastatin ( fluvastatin, atorvastatin, atorvastatin, cervastatin, ulinastatin, and rosuvastatin.
  • the mesenchymal stem cells treated with the STAT3 inhibitor are inhibited the production of proinflammatory factors and inflammatory cytokines, the differentiation and activity of Th1 and Th17 cells is reduced, regulatory T cells (Regulatory T cells) differentiation and activity of cell: Treg) may be enhanced.
  • COPD chronic obstruct
  • the present invention also provides a method for producing mesenchymal stem cells having the effect of preventing and treating immune diseases, comprising the step of treating a signal transducer and activator of transcription 3 (STAT3) inhibitor to mesenchymal stem cells in vitro.
  • STAT3 signal transducer and activator of transcription 3
  • the present invention comprises co-culturing the undifferentiated T cells with mesenchymal stem cells treated with a signal transducer and activator of transcription 3 (STAT3) inhibitor, the differentiation and activity of Undifferentiated T cells into Th1 cells and Th17 cells It provides a way to suppress.
  • STAT3 signal transducer and activator of transcription 3
  • the present invention comprises co-culture of undifferentiated T cells with mesenchymal stem cells treated with a STAT3 (Signal transducer and activator of transcription 3) inhibitor, Regulatory T cells (Treg) of undifferentiated T cells Provided are methods for promoting differentiation and activity of furnaces.
  • STAT3 Synignal transducer and activator of transcription 3
  • Mesenchymal stem cells treated with the STAT3 inhibitor according to the present invention can effectively inhibit the expression and production of inflammatory cytokines and inflammatory factors in mesenchymal stem cells, and when co-cultured with undifferentiated T cells under pathogenic conditions, T cells Cytotoxicity of the cells has the effect of inhibiting the differentiation of Th17 and Th1 cells and promotes the differentiation and activity of immunoregulatory T cells (Tregs), which have the property of inhibiting the function of abnormally activated immune cells and controlling the inflammatory response. The effect is excellent. Therefore, mesenchymal stem cells treated with STAT3 inhibitors can be used as cell therapeutic compositions that can prevent or treat immune diseases such as autoimmune diseases, inflammatory diseases, and transplant rejection diseases caused by abnormalities in the regulation of various immune responses.
  • immune diseases such as autoimmune diseases, inflammatory diseases, and transplant rejection diseases caused by abnormalities in the regulation of various immune responses.
  • Figure 2 shows the results of analyzing the expression level of IL-10, IDO, TGF-beta and HGF in the cells of the mesenchymal stem cells treated with STAT3 inhibitors and mesenchymal stem cells not treated with STAT3 inhibitors.
  • Figure 3 shows the results of analyzing the cell phenotype in mesenchymal stem cells treated with STAT3 inhibitors and mesenchymal stem cells not treated with STAT3 inhibitors.
  • Figure 4 shows the result of confirming whether the STAT3 inhibitor maintains the function of the stem cell itself according to maintaining the differentiation capacity of the treated mesenchymal stem cells.
  • Figure 5a is a factor related to the movement of mesenchymal stem cells, CCR1, CCR2, CCR3, CCR4, CCR7, CCR9 in order to determine whether the adipose-derived mesenchymal stem cells treated with STAT3 inhibitors have the ability to move to the lesion site. And the result of analyzing the expression level of CXCR4 by real-time PCR.
  • Figure 5b is a result confirming the degree of cell migration of mesenchymal stem cells treated with STAT3 inhibitors.
  • FIG. 6 shows IL-17 expression changes in T cells induced by mesenchymal stem cells by co-culturing T cells cultured in Th17 cell differentiation conditions with mesenchymal stem cells treated with STAT3 inhibitor and mesenchymal stem cells not treated with STAT3 inhibitor. It shows the result of analysis.
  • Figure 7 shows the differentiation of Th1 and Th17 cell differentiation of undifferentiated T cells by mesenchymal stem cells by co-cultured T cells with mesenchymal stem cells treated with STAT3 inhibitors and mesenchymal stem cells not treated with STAT3 inhibitors under Th17 cell differentiation conditions, respectively. The results are analyzed by flow cytometry.
  • FIG. 8 is a flow cytometer for Treg cell differentiation of undifferentiated T cells by mesenchymal stem cells by co-culturing T cells with mesenchymal stem cells treated with STAT3 inhibitors and mesenchymal stem cells not treated with STAT3 inhibitors under Th17 cell differentiation conditions. The analysis results are shown.
  • Figure 9 shows the degree of IL-10 production in T cells by mesenchymal stem cells by co-cultured T cells cultured in Th17 cell differentiation conditions with mesenchymal stem cells treated with STAT3 inhibitor and mesenchymal stem cells not treated with STAT3 inhibitor. It shows the result of analysis.
  • Figure 10 shows the results of analyzing the arthritis evaluation index, IgG and inflammatory cytokines in order to determine whether the STAT3 inhibitor is treated with mesenchymal stem cells treated with rheumatoid arthritis.
  • the present invention is characterized by providing a cell therapeutic composition for the prevention or treatment of immune diseases, including mesenchymal stem cells treated with a STAT3 (Signal transducer and activator of transcription 3) inhibitor as an active ingredient.
  • STAT3 Synignal transducer and activator of transcription 3
  • cell therapies as a therapeutic agent for various diseases including cancer as well as the conventional immune diseases, and the cell therapy technology using stem cells are being developed in particular, the cell therapy has the advantage of less side effects than the conventional compound treatment There is a problem of low therapeutic effect.
  • the present inventors are developing a cell therapy for the treatment of immune diseases with a low therapeutic side effect and excellent therapeutic effect.
  • the present invention can effectively prevent and treat immune diseases. Found.
  • STATs are transcription factors having seven subunit forms of STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.
  • STATs include N-terminal domain (ND), coiled-coil domain (CCD), DNA-binding domain (DBD), linker domain (LD), Src homology 2 (SH2) and transcriptional activation domain (TAD) It shares six distinct structural domains, among which STAT3 has critical tyrosine and serine residues (Tyrosine 705, Serine 727 residues for STAT3) at the C-terminus that is phosphorylated by activation.
  • STAT3 is continuously activated through various pathways and promotes tumor formation, and STAT3 is also used for various cytokines, growth factor-interferons, and epidermis.
  • Growth factor platelet-derived growth factor, interleukin5, interleukin6, hepatocyte growth factor, leukemia inhibitory factor (LIF), bone morphogenetic protein2, hormone leptin, carcinogenic proteins such as Src and Ras in response to Tyrosine 705, Serine 727 It is activated through phosphorylation at two residues of.
  • LIF leukemia inhibitory factor
  • STAT3 is a transcriptional regulator involved in the transcription of several genes in human cells. Normally, STAT3 in the cytoplasm moves into the nucleus in response to signaling by cytokines or growth factors from the outside. Regulate genes for development, differentiation, growth, survival, angiogenesis, and immune function, but if STAT3 is abnormal, STAT3 plays an important role in cancer development. A large number of malignancies, animal model experiments, and activated STAT3 have been found in cancer patients, and STAT3 regulates the expression of many different genes that cause and develop cancer.
  • STAT3 is known to inhibit the expression of mediators necessary for immune activation against tumor cells, and the activity of STAT3 also promotes the production of factors that activate STAT3 in various immune cells while altering gene expression programs. It also suppresses the reaction.
  • the immune system controls specific immune responses to autoantigens under normal conditions, and also suppresses immune responses against external antigens.
  • the pregnant woman's response to fetuses and immunity to chronic infections Reaction are known to be induced by clonal deletion, clone anergy and active control by immunoregulatory T cells (Tregs) as a mechanism by which antigen-specific immunotolerance can be induced.
  • Tregs immunoregulatory T cells
  • Investigation of some patients who accidentally acquired immunotolerance against or experimentally induced animal models showed that all three of these mechanisms are involved in graft-immunity tolerance. It is attracting attention as an important cell involved in controlling almost all immune responses of the living body such as autoimmune, tumoral immunity, infectious immune response as well as immune response.
  • immunoregulatory T cells ie immunoregulatory T lymphocytes (Tregs), whose presence has recently been identified, can be largely divided into natural and adaptive Treg cells, and CD4 + CD25 + T cells, which are natural Tregs, are cells.
  • Tregs immunoregulatory T lymphocytes
  • CD4 + CD25 + T cells which are natural Tregs
  • the mechanism of immunosuppression of this cell is not yet known, but it has recently been discovered that the expression control factor of the gene, Foxp3, plays an important role in the differentiation and activity of the cell.
  • peripheral natural T cells can be differentiated into cells that exhibit immunosuppressive effects upon stimulation of autologous or external antigens under certain circumstances, which are called adaptive or inducible Tregs and secrete IL-10. These include Tr1, Th3 and CD8 Ts that secrete TGF- ⁇ .
  • T cells are also differentiated into Th17 cells through differentiation in addition to Treg cells.
  • Th17 cells are formed in the presence of TGF- ⁇ in common with Treg cells, but IL- for Treg cells.
  • Th17 cells are characterized by differentiating in the presence of IL-6 with TGF- ⁇ and secreting IL-17.
  • Th17 cells are characterized by cytotoxicity, which maximizes the signal of the inflammatory response and accelerates disease progression. Therefore, inhibition of differentiation or activity into Th17 cells is one of the ways to treat immune diseases.
  • the present inventors have developed a cell therapy with excellent therapeutic effect as a previously developed immune disease treatment agent, mesenchymal stem cells cultured by treating the mesenchymal stem cells with an inhibitor that can inhibit the expression and activity of STAT3 is immune disease
  • mesenchymal stem cells treated with STAT3 inhibitors inhibit the production of inflammatory factors and inflammatory cytokines, and differentiate Th1 and Th17 cells. And activity was reduced, it was confirmed that the differentiation and activity of Regulatory T cells (Treg) is enhanced. Therefore, the present invention can provide a cell therapeutic composition for the prevention or treatment of immune diseases, including mesenchymal stem cells treated with a STAT3 (Signal transducer and activator of transcription 3) inhibitor as an active ingredient.
  • STAT3 Simal transducer and activator of transcription 3
  • the STAT3 inhibitors that can be used in the present invention include, but are not limited to, STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 (2H) -trione), AG-490 ((E) -2-Cyano-3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide), Atiprimod; 3- (8,8-dipropyl-3-azaspiro [4.5 ] decan-3-yl) -N, N-diethylpropan-1-amine), auranofin (3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), orosiomaleate (Aurothiomalate; Sodium 2- (auriosulfanyl) -3-carboxypropanoate), BMS-354825 (Dasatinib; N- (2-chloro-6
  • the STAT3 inhibitor is treated with a concentration of 0.1uM ⁇ 100uM in mesenchymal stem cells of 1x10 5 ⁇ 1x10 7 cells to incubate for 24 to 72 hours at a temperature of 37 °C to obtain mesenchymal stem cells excellent in the treatment of immune diseases. have.
  • statin-based compounds are cilastatin, nystatin, lovastatin, lovastatin, somatostatin, pravastatin, simvastatin, fluvastatin It may be selected from the group consisting of atorvastatin, atorvastatin, cervastatin, cerinastatin, ulinastatin, and rosuvastatin.
  • mesenchymal stem cells used in the present invention are stem cells that are separated from bone marrow, blood, dermis and periosteum, and are pluripotent capable of differentiating into various cells such as adipocytes, chondrocytes and bone cells. ) Or multipotent cells.
  • the mesenchymal stem cells may be mesenchymal stem cells of animals, preferably mammals, and more preferably human, and are mesenchymal stem cells of mice according to an embodiment of the present invention.
  • Mesenchymal stem cells are present in very small amounts in bone marrow and the like, but the process of isolating and culturing them is well known in the art and is disclosed, for example, in US Pat. No.
  • the mesenchymal stem cells can be obtained by separating them from the hematopoietic stem cells of bone marrow according to a known method and then proliferating without losing differentiation ability.
  • mesenchymal stem cells are isolated from mammalian, preferably human, mesenchymal stem cell sources, such as blood or bone marrow, including humans or mice.
  • the bone marrow can be extracted from the tibia, femur, spinal cord or iliac bone. Cells are then obtained from the bone marrow and these cells are cultured in a suitable medium. Suspension cells are removed during the culturing process and passaged cells attached to the culture plate to obtain finally established mesenchymal stem cells.
  • the medium used in the above process any medium commonly used for culturing stem cells can be used.
  • the medium contains serum (eg fetal calf serum, horse serum and human serum).
  • Mediums that can be used in the present invention are, for example, RPMI series, Eagles' MEM (Eagle's minimum essential medium, Eagle, H. Science 130: 432 (1959)), ⁇ -MEM (Stanner, CP et al., Nat New Biol. 230: 52 (1971)), Iscove's MEM (Iscove, N. et al., J. Exp. Med. 147: 923 (1978)), 199 medium (Morgan et al., Proc. Soc.Exp. Bio.Med., 73: 1 (1950)), CMRL 1066, RPMI 1640 (Moore et al., J. Amer. Med. Assoc.
  • the medium may include other components such as antibiotics or antifungal agents (eg, penicillin, streptomycin), glutamine, and the like. General descriptions of media and cultures are described in R. Ian Freshney, Culture of Animal Cells, Alan R. Liss, Inc., New York (1984), which is incorporated herein by reference.
  • identification of mesenchymal stem cells can be performed, for example through flow cytometry.
  • flow cytometry is performed using specific surface markers of mesenchymal stem cells.
  • mesenchymal stem cells show a positive response to CD44, CD29 and / or MHC class I.
  • the mesenchymal stem cells used in the present invention show a positive response to surface markers CD44, CD29 and MHC class I, and negative for CD14, CD34, CD45, CD54, MHC class II and CD11b.
  • Indicates a reaction Indicates a reaction.
  • the term positive reaction used while referring to stem cells and surface markers means that the antibody specifically binds to the surface antigens of the stem cells when the stem cells are treated with an antibody against the surface markers.
  • mesenchymal stem cells treated with the STAT3 inhibitor of the present invention inhibit or reduce the differentiation of undifferentiated T cells into Th17 cells that secrete inflammatory cytokines, or control T cells that can normally regulate excessive immune responses.
  • the STAT3 inhibitor of the present invention inhibit or reduce the differentiation of undifferentiated T cells into Th17 cells that secrete inflammatory cytokines, or control T cells that can normally regulate excessive immune responses.
  • the activity means that all the mechanisms of the regulatory T cells (Treg), ie, Treg cells including both natural and adaptive Treg cells, are promoted or promoted in vivo.
  • Treg regulatory T cells
  • the immunomodulatory action such as an immunosuppressive reaction is promoted or promoted so that the immune response in vivo is maintained in a normal state.
  • the amplification refers to the differentiation and proliferation of undifferentiated T cells into regulatory T cells
  • 'differentiation' is a phenomenon that the structure or function of each other during the division and growth of cells, that is, the organism Cells or tissues are changed in form or function in order to perform a given task
  • 'proliferation' refers to the division of cells and homogeneous ones, which usually increase the number of cells in the body of a multicellular organism. I say going.
  • the immune disease means a disease in which components of the mammalian immune system cause, mediate or otherwise contribute to the pathology of the mammal.
  • stimulation or interruption of an immune response may include any disease that has a compensatory effect on the progression of the disease, and in the present invention may include diseases caused by an overactive immune response.
  • immune diseases include, but are not limited to, autoimmune diseases; Inflammatory diseases; And transplant rejection of cells, tissues, or organs.
  • the immune disease of the present invention is not limited thereto, but is not limited thereto, rheumatoid arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, late organ transplantation, and chronic Post transplantation late and chronic solid organ rejection, Multiple Sclerosis, systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, polymyositis, scleroderma (scleroderma), Addison disease, vitiligo, pernicious anemia, glomerulonephritis and pulmonary fibrosis, inflammatory growth disease (Inflammatory Bowel Imses), autoimmune diabetes (Autoimmune) Diabetes, Diabetic retinopathy, Rhinitis, Ischemia-reperfusion injury, Post-angioplasty r estenosis, Chronic obstructive pulmonary diseases (COPD), Graves disease, Gastrointestinal allergies, Conjunctivitis, Atherosclerosis, Coronary artery disease An
  • an immune response occurs to autoantigens, which causes the attack of one's own tissue.
  • the disease caused by this process is called an autoimmune disease. .
  • Inflammatory diseases include excessive necrosis factor- ⁇ (TNF- ⁇ ) and IL-1 (interleukin- ⁇ ) secreted by immune cells such as macrophages due to excessive stimulation of the human immune system due to harmful stimuli such as inflammation-inducing factors or irradiation.
  • TNF- ⁇ necrosis factor- ⁇
  • IL-1 interleukin- ⁇ secreted by immune cells such as macrophages due to excessive stimulation of the human immune system due to harmful stimuli such as inflammation-inducing factors or irradiation.
  • inflammatory substances inflammatory cytokines
  • IL-6 IL-6
  • prostagladin luecotriene
  • nitric oxide nitric oxide
  • T cell The major mediator of GCC is T cell, which is induced by the T cell receptor to recognize the major histocompatibility complex (MHC) expressed in the graft.
  • MHC major histocompatibility complex
  • immunosuppressive agents are used to reduce the graft immune rejection response.
  • the common purpose of these immunosuppressive agents is to suppress T cell-mediated immune responses against the graft.
  • transplantation is achieved by suppressing the immune response using regulatory T cells. Attempts have been made to treat rejection diseases.
  • composition according to the present invention can be used as a pharmaceutical composition, preferably a cell therapy composition that can prevent or treat immune diseases.
  • treatment means to reverse, alleviate, inhibit the progression of, or prevent a disease or condition to which the term applies, or one or more symptoms of the disease or condition, unless otherwise stated,
  • treatment or therapy of immune diseases in a mammal may comprise one or more of the following:
  • composition for preventing or treating an immune disease according to the present invention may include mesenchymal stem cells treated with a pharmaceutically effective amount of a STAT3 inhibitor alone or may include one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the pharmaceutically effective amount herein refers to an amount sufficient to prevent, ameliorate and treat the symptoms of an immune disease.
  • the pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not cause an allergic reaction such as gastrointestinal disorders, dizziness or the like when administered to humans.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • composition for preventing or treating immune diseases according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient is determined by the route of administration, age, sex, It may be appropriately selected according to various factors such as the weight and the severity of the patient, and the composition for preventing or treating an immune disease according to the present invention is combined with a known compound having the effect of preventing, ameliorating or treating the symptoms of an immune disease. It may be administered, preferably parenterally. When administered parenterally, the pharmaceutical composition of the present invention may be administered by intravenous infusion, subcutaneous infusion, intramuscular infusion, intraperitoneal infusion, or the like.
  • Suitable dosages of the pharmaceutical compositions of the present invention may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response to the recipient. Can be.
  • the dose of the pharmaceutical composition of the present invention is preferably from 1 x 10 3 per 1 - a 1 x 10 12 cells / kg.
  • the present invention can provide a method for producing mesenchymal stem cells having the effect of preventing and treating immune diseases, comprising the step of treating a signal transducer and activator of transcription 3 (STAT3) inhibitor to the mesenchymal stem cells in vitro. And co-culturing the undifferentiated T cells with mesenchymal stem cells treated with a signal transducer and activator of transcription 3 (STAT3) inhibitor. It can provide a method of suppressing.
  • STAT3 signal transducer and activator of transcription 3
  • the present invention comprises co-culturing undifferentiated T cells with mesenchymal stem cells treated with a STAT3 (Signal transducer and activator of transcription 3) inhibitor, to regulated T cells (Treg) Methods for promoting differentiation and activity can be provided.
  • STAT3 Synignal transducer and activator of transcription 3
  • a method of reducing or inhibiting differentiation of undifferentiated T cells into Th17 cells in vitro and a method of activating regulatory T cells include STAT3 in a medium for culturing the T cells.
  • the inhibitor-treated mesenchymal stem cells may be added and cultured together, or the medium for culturing the T cells may be cultured by treating the STAT3 inhibitor and mesenchymal stem cells together.
  • the present inventors conducted the experiment as follows to determine whether the STAT3 inhibitor is effective in inhibiting STAT3 activity and inhibiting inflammation and tumor factor at the same time.
  • the adipose tissue obtained by liposuction or the adipose tissue obtained after surgery is washed 10 times or more with PBS containing 10% penicillin-streptomycin to remove blood and foreign matter, and then the tissue is chopped to 0.2-0.3 g. Cut.
  • the solution was added to a 0.2% collagenase (Roche, Sandhofer Strasse, Mannheim, Germany) solution and reacted at 37 ° C. in a water bath at 100 rpm for 1 hour. After separating the solution layer and the undecomposed fragments by collagenase using a 100 ⁇ m mesh, an equal amount of PBS was added to the separated collagenase solution. Subsequently, centrifugation was performed at 4 ° C.
  • MSC basal medium (Cambrex, Walkersville, MD, USA), mesenchymal cell growth aid (Cambrex, Walkersville, MD, USA), 4 mM to remove remaining collagenase solution from submerged MSC L-glutamine and penicillin (0.025 unit / 500 mL) / streptomycin (0.025 mg / 500 mL)] was added again centrifuged for 5 minutes at 4 °C, 1200 rpm.
  • MSCGM is a medium based on Dulbecco's modified Eagle's medium (DMEM) containing fetal calf serum. Subsequently, the supernatant was removed, and the obtained MSC was inoculated in a culture plate and incubated in a 37 ° C., 5% CO 2 incubator with MSCGM. Incubate while replacing the culture medium every other day.
  • DMEM Dulbecco's modified Eagle's medium
  • the isolated and cultured mesenchymal stem cells were treated with STA-21, a STAT3 inhibitor, and analyzed for STAT3 expression in mesenchymal stem cells.
  • adipose derived mesenchymal stem cells were treated with 5 mM and 10 ⁇ M STA-21 drugs, respectively, based on the number of 2 ⁇ 10 5 cells, and cultured under 37 ° C. to prepare mesenchymal stem cells treated with STAT3 inhibitors.
  • mesenchymal stem cells that were not treated with the STAT3 inhibitor were used as controls, and the amount of STAT3 in the mesenchymal stem cells treated with the STAT3 inhibitor was analyzed by Western blot.
  • HMGB-1, IL-6, IL-1beta was significantly reduced by 2 to 10 times compared to the group without inhibitor.
  • the present inventors have found that by treating the mesenchymal stem cells with STAT3 inhibitors, the mesenchymal stem cells with STAT3 inhibition can be used as cell therapy for the treatment of immune diseases.
  • the present inventors first isolated and cultured mesenchymal stem cells from peripheral blood in order to investigate the efficacy of STAT3 inhibitor-treated mesenchymal stem cells (MSCs), that is, to separate the PBMC after collecting 50cc of blood from normal people After incubation for 5 days in a-MEM medium containing 20% FBS cells were removed on the culture medium. Thereafter, the medium was changed at three-day intervals, and cells were removed from the culture plate and cultured again according to the degree of proliferation, and this culture was performed three times (passage 3) to obtain mesenchymal stem cells from peripheral blood. In addition, cell markers were identified to confirm whether the obtained cells were mesenchymal stem cells. As a result, the cells isolated by confirming that CD105 + CD29 + CD44 positive and CD34, CD45, HLA-DR negative were identified as mesenchymal stem cells. Confirmed.
  • MSCs STAT3 inhibitor-treated mesenchymal stem cells
  • the isolated mesenchymal stem cells were treated with STAT3 inhibitors AG-490 and sta-21 in amounts of 5uM and 10uM based on 1x10 5 cells of mesenchymal stem cells.
  • IL-10, IDO, TGF-beta and HGF genes related to immunomodulatory activity were analyzed in mesenchymal stem cells treated with STAT3 inhibitors and mesenchymal stem cells not treated with STAT3 inhibitors.
  • the amount of mRNA expressed in the cell was analyzed by real-time PCR, and the primer sequences used in PCR to analyze the expression level of each gene are as follows.
  • mesenchymal stem cells treated with STAT3 inhibitors such as AG-490 and sta-21 showed up to a 20-fold increase in IL-10 expression compared to mesenchymal stem cells not treated with STAT3 inhibitors.
  • IDO expression was up to 2 times
  • TGF-beta expression was up to 7 times
  • HGF expression was up to 10 times higher.
  • the present inventors performed a phenotypic analysis to determine whether the mesenchymal stem cells treated with the STAT3 inhibitors did not change in the phenotype of the mesenchymal stem cells and the cells not treated with the inhibitors, that is, the culture medium to which the STAT3 inhibitors were added and the inhibitors were used. Each cultured cell was removed from the culture medium without addition, and FACS analysis was performed using an antibody labeled with streaks related to the phenotype of mesenchymal stem cells. CD105, CD29 and CD44 were used as positive markers of mesenchymal stem cells, and CD45 and HLA-DR were used as negative markers.
  • the differentiation test was performed on adipocytes, bone cells, and chondrocytes using differentiation-inducing culture medium of different compositions.
  • Fat cells, bone cells, cartilage cells, each of the differentiation culture medium into a dedicated culture within the mesenchymal stem cells were used for differentiation kit (R & D, # sc006) , then it gave crushing the cells in 24-well plates, each 1x10 4 Kit 3 Every 4 days the medium was changed and incubated for 2-3 weeks. Then, after staining with each detection Ab, DAPI, it was observed by fluorescence microscope.
  • adipose-derived mesenchymal stem cells treated with STAT3 inhibitors are capable of cell migration, they can move to the lesion site, which are factors related to the movement of mesenchymal stem cells, CCR1, CCR2, CCR3, CCR4, CCR7, and CCR9. And the expression level of CXCR4 was analyzed by real-time PCR.
  • CCR2 (about 3 times), CCR3 (about 3 times), CCR4 (about 3 times), in mesenchymal stem cells treated with STAT3 inhibitors compared to the group without treatment with STAT3 inhibitors,
  • the expression of CCR7 (about 5 fold) and CCR9 (about 4 fold) was significantly increased.
  • the present inventors used the ct-3422 product (pore size 8 micro M, polycarbonate) to determine whether the migration ability is increased by increasing cytokine expression, MSC 1x10 on the upper chamber (upper chamber) 4 / 100ul Serum Free-DMEM was added to the lower chamber (lower chamber) was added 300ul of serum free media containing 10ng / ml of SDF-1 and incubated for one day, the number of cells moved the next day.
  • the present inventors have excellent immunomodulatory ability in the co-culture of T cells and mesenchymal stem cells treated with the STAT3 inhibitor of the present invention under Th17 conditions, which are inflammation and disease causing conditions. In order to investigate whether it can be used as a cell therapy for immune diseases, the following experiment was performed.
  • CD4 T cells were isolated from DBA1 / J normal mouse group, and CD3 0.5ug / ml, CD28 1ug / ml, IL-6 20ng / ml, TGF-b 2ng / ml, IFNr mAb, IL- Cells were incubated with differentiation conditions to Th17 cells by treatment with 4 mAb. Thereafter, T cells cultured under Th17 differentiation conditions were co-cultured with the STAT3 inhibitor-treated mesenchymal stem cells used in Example 1, and ELISA was performed to examine the production of IL-17 and IL-10 in the co-cultured mesenchymal stem cells. The degree of Th1 and Th17 cell differentiation and Treg cell differentiation were analyzed by flow cytometry.
  • Flow cytometry analysis was performed using anti-CD4-percp (h1, Th17) and anti-CD4-percp and The cells were treated with anti-CD25-APC (for Treg irradiation) and reacted at 4 ° C. for 30 minutes, followed by permeabilization of the cells, followed by anti-IL-17-PE, anti-IFNr-FITC and Ab anti-Foxp3-PE. After each reaction with fluorescence Ab, it was analyzed by flow cytometry. In addition, mesenchymal stem cells not treated with STAT3 inhibitors were used as controls.
  • inflammatory cytokine IL in T cells was co-cultured with T cells when mesenchymal stem cells treated with STAT3 inhibitors were co-cultured with T cells even under Th17 cell differentiation conditions.
  • the production of -17 was found to be significantly reduced compared to the control, and the production of IL-10, a cytokine with immunomodulatory activity, was increased.
  • Th1 and Th17 cell differentiation was inhibited by mesenchymal stem cells treated with STAT3 inhibitors, and Th1 and Th17 cell differentiation was suppressed more effectively than mesenchymal stem cells not treated with STAT3 inhibitors.
  • Treg cells with immunomodulatory ability were more differentiated by mesenchymal stem cells treated with STAT3 inhibitors, and Treg cells were increased more than mesenchymal stem cells without STAT3 inhibitors. (See FIGS. 7 and 8).
  • the present inventors conducted the following experiments to determine whether the treatment of rheumatoid arthritis in an animal model of rheumatoid arthritis through induction of autoantigen activity of mesenchymal stem cells treated with STAT3 inhibitors.
  • type II collagen (CII) and CFA (adjuvant) 1: 1 were mixed in DBA / 1J mice, and 100 ⁇ g of CII per mouse was injected at 50 ul into the tail base. Two weeks later, the mixture was mixed with CII and IFA 1: 1. Arthritis animals were prepared by a second injection at 100 ug / 50 ul.
  • Arthritis-induced mice were injected with mesodermal stem cells treated with intravenous 1x10 6 or mesenchymal stem cells treated with STAT3 inhibitors, three times a week, one week after arthritis-induced mice. And arthritis evaluation was performed. Three weeks after the first inoculation, three observers, who did not know the contents of the experiment, evaluated the severity of the joint inflammation twice a week and observed it for up to 61 days. At this time, arthritis evaluation was averaged by dividing the scores of the three legs except the legs to which CII / CFA was administered at the second dose per dividing according to the following scale, divided by three, and then obtained by three observers in each animal model. The average value divided by summing was used. The scores and criteria according to arthritis evaluation are as follows.
  • IgG antibodies were applied to a 96-well microtitier plate for 2 hours at room temperature, and then diluted 50 ⁇ l of the diluted serum sample was reacted at room temperature for 1 hour. After the reaction, the solution was washed three times with TBS (pH 8.0) solution containing 0.05% Tween 20 (Amresco), and then the IgG antibody was reacted for 1 hour. After washing with the above solution, the TMB + H 2 O 2 system (KPL , Gaithersburg, MD). This was read as absorbance at 450 nm, and the results of antibody measurements were expressed as absorbance itself.
  • TBS pH 8.0
  • Amresco Tween 20
  • the mouse group treated with mesenchymal stem cells and STAT3 inhibitors showed a significant decrease in IgG antibody secretion (see FIG. 10).
  • the production of inflammatory cytokines, IL-17 and TNF-a was analyzed.
  • LPS (10 mg / ml) was stimulated.
  • Splenocytes were stimulated by administering mesenchymal stem cells treated with STAT3 inhibitors.
  • the cultured supernatant was collected and confirmed the expression level of IL-17 and TNF-a using mouse TNF-a, sandwich ELISA. Specifically, first, monoclonal anti-TNF-a 2 ⁇ g / in a 96-well plate (well plate) The reaction was reacted overnight at 4 ° C. with mL, and after the reaction, non-specific binding was blocked with blocking solution (1% BSA / PBST). IL-17 recombinant and TNF-a recombinant were used as a standard by diluting each successive half of each. Cell culture supernatants were added and reacted at room temperature for 2 hours.
  • biotinylated anti-TNF-a was reacted at room temperature for 2 hours, washed four times, and diluted with ExtraAvidin-Alkaline Phosphatase conjugate, and reacted at room temperature for 2 hours. Then, PNPP / DEA solution was added and developed. After absorbance, absorbance was measured at 405 nm.
  • mice treated with mesenchymal stem cells and STAT3 inhibitors were more significantly inhibited in the production of inflammatory cytokines, IL-17 and TNF-a, compared with the mice injected with mesenchymal stem cells. (See FIG. 10).
  • the present inventors experimented as follows to determine the immunomodulatory ability of the STAT3 inhibitor to the lupus animal model cells of adipose derived mesenchymal stem cells treated.

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Abstract

La présente invention concerne une composition cellulaire thérapeutique comprenant des cellules souches mésenchymateuses, qui ont été traitées avec un inhibiteur de STAT3, en tant qu'ingrédient actif pour la prévention ou le traitement de maladies immunitaires. Les cellules souches mésenchymateuses traitées avec un inhibiteur de STAT3 selon la présente invention sont caractérisées par : leur capacité à supprimer efficacement l'expression et la production de cytokines inflammatoires et d'agents induisant une inflammation dans les cellules souches mésenchymateuses ; leur effet d'inhibition de la différenciation de lymphocytes T en cellules Th1 et Th17 cytotoxiques pendant la co-culture avec des lymphocytes T non différenciés dans une condition provoquant une maladie ; et leur excellent effet de promotion de la différenciation et de l'activité de lymphocytes T immunorégulateurs (Treg) ayant les propriétés de suppression d'une fonction des cellules immunologiques anormalement activées et de commande d'une réponse inflammatoire. Ainsi, les cellules souches mésenchymateuses traitées avec un inhibiteur de STAT3 peuvent être utilisées sous la forme d'une composition cellulaire thérapeutique capable de prévenir ou de traiter des maladies immunitaires telles que des maladies auto-immunes, des maladies inflammatoires et le rejet de greffe résultant d'un trouble de la régulation de diverses réponses immunitaires.
PCT/KR2014/010021 2014-06-17 2014-10-23 Composition comprenant des cellules souches mésenchymateuses traitées avec un inhibiteur de stat3 en tant que principe actif pour la prévention ou le traitement de maladies immunitaires WO2015194710A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2018182612A1 (fr) * 2017-03-30 2018-10-04 Progenity Inc. Procédés et dispositifs pouvant être ingérés pour la libération régio-spécifique de cellules souches au site d'une maladie du tractus gastro-intestinal

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