WO2011105394A1 - 制御性樹状細胞の作製方法 - Google Patents
制御性樹状細胞の作製方法 Download PDFInfo
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- WO2011105394A1 WO2011105394A1 PCT/JP2011/053906 JP2011053906W WO2011105394A1 WO 2011105394 A1 WO2011105394 A1 WO 2011105394A1 JP 2011053906 W JP2011053906 W JP 2011053906W WO 2011105394 A1 WO2011105394 A1 WO 2011105394A1
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- cells
- triazolo
- regulatory dendritic
- dendritic cells
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Definitions
- the present invention is a control used for the prevention and treatment of diseases such as transplant rejection, graft-versus-host disease, autoimmune diseases, allergic diseases, chronic inflammatory diseases and sepsis caused by abnormal and excessive responses of the immune system.
- the present invention relates to a method for producing a dendritic cell. More particularly, the present invention relates to [1,2,4] triazolo [1,5-a] pyrimidine derivatives, particularly (S)-(+)-1- (5-hydroxy-1,5-dimethylhexyl). ) Method for producing regulatory dendritic cells using 3- [7- (4-methoxyphenyl)-[1,2,4] triazole [1,5- ⁇ ] pyrimidin-2-yl] urea (NK026680) About.
- this invention relates to the pharmaceutical composition or pharmaceutical kit containing the regulatory dendritic cell produced by the said method, and the said regulatory dendritic cell.
- the invention further relates to the use of [1,2,4] triazolo [1,5-a] pyrimidine derivatives for the production of regulatory dendritic cells.
- Dendritic cells are antigen-presenting cells having dendrites and are widely present as immature dendritic cells in peripheral non-lymphoid tissues and lymphoid tissues. In inflammatory tissues that are invaded by foreign antigens such as microorganisms, viruses, and foreign substances, these antigens are phagocytosed to differentiate into mature dendritic cells and transferred to the secondary lymphoid tissue.
- mature dendritic cells give antigen stimulation and costimulation to naive T cells, induce differentiation into antigen-specific effector T cells, and induce an immune response.
- dendritic cells are powerful antigen-presenting cells that connect innate and acquired immunity.
- dendritic cells in which the expression of costimulatory molecules is decreased even in an inflammatory environment, and these dendritic cells suppress T cells in a suppressive manner and induce immune tolerance against self tissues and the like. It has been suggested. Such dendritic cells are called regulatory dendritic cells. Immune cell therapy using regulatory dendritic cells showed therapeutic effects by inducing antigen-specific unresponsive T cells and regulatory T cells in graft versus host disease, autoimmune disease, and allergic disease models in mice ( Non-patent documents 1, 2, and 3). Furthermore, in a mouse sepsis model, regulatory dendritic cells inhibited the production of inflammatory cytokines through the production of IL-10 and showed a life-prolonging effect (Non-patent Document 4).
- Patent Document 1 discloses a method for inducing human immunoregulatory dendritic cells by culturing human dendritic cells or their progenitor cells in vitro with cytokines containing at least IL-10 and TGF- ⁇ , and obtained by the method. Human immunoregulatory dendritic cells have been described. Patent Document 2 attempts to use regulatory dendritic cells as a promoter for IL-10 production and to systemic inflammatory response syndrome.
- Non-Patent Document 1 cytokines and the like containing IL-10 and TGF- ⁇ are used for the production of regulatory dendritic cells reported to date. Since it is produced from genetically modified organisms such as Escherichia coli, there are problems of production cost and safety that prevent mass preparation.
- [1,2,4] triazolo [1,5-a] pyrimidine derivatives are substances that inhibit the function of dendritic cells and have an inhibitory effect on mouse delayed-type hypersensitivity reactions.
- Patent Document 4 one of its derivatives is (S)-(+)-1- (5-hydroxy-1,5-dimethylhexyl) -3- [7- (4-methoxyphenyl)-[1,2,4] triazolo.
- NK026680 When dendritic cells are cultured in the presence of [1,5- ⁇ ] pyrimidin-2-yl] urea (hereinafter referred to as “NK026680”), the expression of costimulatory molecules decreases, and NK026680 is a graft versus host disease model. And an effect on an autoimmune vasculitis model (Non-patent Documents 5 and 6).
- the present invention has an object to be solved to establish a method capable of safely and easily producing a large amount of regulatory dendritic cells. Furthermore, this invention makes it the problem which should be solved to provide a control dendritic cell useful for the prevention and treatment of the immune system disease which maintains a patient's QOL.
- the present inventors have cultured cells that can be induced into regulatory dendritic cells in the presence of [1,2,4] triazolo [1,5-a] pyrimidine derivatives. As a result, it was found that regulatory dendritic cells can be produced, and the present invention has been completed.
- a method for producing regulatory dendritic cells comprising culturing cells inducible into regulatory dendritic cells in the presence of a [1,2,4] triazolo [1,5-a] pyrimidine derivative.
- the [1,2,4] triazolo [1,5-a] pyrimidine derivative is converted to (S)-(+)-1- (5-hydroxy-1,5-dimethylhexyl) -3- [7-
- the method for producing a regulatory dendritic cell according to (1) which is (4-methoxyphenyl)-[1,2,4] triazolo [1,5- ⁇ ] pyrimidin-2-yl] urea.
- a method for producing dendritic cells. The method for producing a regulatory dendritic cell according to any one of (1) to (5), comprising culturing the cell in the presence of GM-CSF and IL-4. (7) The method for producing a regulatory dendritic cell according to any one of (1) to (6), comprising culturing the cell in the presence of TNF- ⁇ and / or LPS.
- Regulatory dendritic cells produced by the production method according to any one of (1) to (7).
- (9) Compared to cells obtained by culturing cells inducible to regulatory dendritic cells in the absence of [1,2,4] triazolo [1,5-a] pyrimidine derivatives, CD40, The regulatory dendritic cell according to (8), wherein the expression level of CD80 and CD86 is low.
- (10) Compared with cells obtained by culturing cells inducible to regulatory dendritic cells in the absence of [1,2,4] triazolo [1,5-a] pyrimidine derivatives, IL- The regulatory dendritic cell according to (8) or (9), wherein the production amount of 6 and IL-12p40 is low.
- the regulatory dendritic cell according to any one of (8) to (10), which has a low ability of inducing T cell activation to an antigen.
- a pharmaceutical composition or a pharmaceutical kit comprising the regulatory dendritic cell according to any one of (8) to (11). (13) used for the prevention and / or treatment of transplant rejection, graft-versus-host disease, autoimmune disease, allergic disease, chronic inflammatory disease and sepsis caused by abnormal and excessive responses of the immune system ( The pharmaceutical composition or pharmaceutical kit according to 12).
- a control dendritic cell induction reagent comprising a [1,2,4] triazolo [1,5-a] pyrimidine derivative.
- the [1,2,4] triazolo [1,5-a] pyrimidine derivative is converted to (S)-(+)-1- (5-hydroxy-1,5-dimethylhexyl) -3- [7-
- the control dendritic cell induction reagent according to (16) which is (4-methoxyphenyl)-[1,2,4] triazolo [1,5- ⁇ ] pyrimidin-2-yl] urea.
- the [1,2,4] triazolo [1,5-a] pyrimidine derivative is useful for inducing regulatory dendritic cells from mononuclear cells contained in peripheral blood cells, bone marrow cells, etc. in vitro. is there.
- the [1,2,4] triazolo [1,5-a] pyrimidine derivative is a low-molecular compound that has low production costs and can ensure mass production and safety.
- a large amount of regulatory dendritic cells can be prepared at low cost without using expensive and unstable recombinant cytokines.
- the drug used for production does not remain in the regulatory dendritic cells of the present invention, bone marrow suppression, organ transplantation, autoimmune disease, allergy without causing side effects caused by the drug used for production It is very effective in the prevention and treatment of diseases caused by abnormalities and excessive responses of immune systems such as diseases and shocks.
- FIG. 1 shows the 3H-TdR uptake of regulatory dendritic cells (NK-DC), untreated dendritic cells (CTR-DC) and immature dendritic cells (unstim-DC) of the present invention.
- Black circles indicate NK-DC
- white circles indicate CTR-DC
- x indicates unstim-DC.
- FIG. 2 shows C3He / J mice transplanted with C57He / 6 mice transplanted with C3He / J mice into which regulatory dendritic cells (NK-DC) and untreated dendritic cells (CTR-DC) were transferred, respectively.
- the survival rate of J mice is shown.
- a solid line indicates NK-DC, and a dotted line indicates CTR-DC.
- regulatory dendritic cells for example, dendritic cells or progenitor cells thereof
- regulatory dendritic cells can be generated by treatment with cytokines and / or inflammatory stimulators.
- cytokines and / or inflammatory stimulators e.g., IL-4, [1,2,4] triazolo [1,5-a] pyrimidine derivatives
- cytokines and / or inflammatory stimulators e.g., TNF- ⁇ , LPS, etc.
- the order of stimulation of these cytokines and / or inflammatory stimuli and [1,2,4] triazolo [1,5-a] pyrimidine derivatives is not particularly limited, and the order of stimulation is performed in any order.
- regulatory dendritic cells can be prepared.
- monocytes are cultured in vitro in the presence of GM-CSF and IL-4 to differentiate monocytes into dendritic cells, and the resulting dendritic cells are [1,2,4] triazolo [1 , 5-a] pyrimidine derivatives can induce regulatory dendritic cells.
- monocytes may be first stimulated with GM-CSF and IL-4 to differentiate into dendritic cells and then stimulated with [1,2,4] triazolo [1,5-a] pyrimidine derivatives.
- GM-CSF, IL-4, [1,2,4] triazolo [1,5-a] pyrimidine derivatives may be stimulated simultaneously.
- [1,2,4] triazolo [1,5-a] pyrimidine derivatives and cytokines for example, IL-10 and TGF- ⁇
- mature regulatory dendritic cells can be obtained by applying inflammatory stimuli such as TNF- ⁇ and LPS.
- cytokines include those having an action of inducing differentiation of dendritic cells such as GM-CSF, IL-4, IL-10, and TGF- ⁇ .
- inflammatory stimulating substances include lipopolysaccharides typified by LPS and cytokines that give inflammatory stimuli such as TNF- ⁇ .
- Dendritic cells can be obtained by culturing monocytes in the presence of GM-CSF and / or IL-4 as described above.
- the monocytes at this time may be derived from peripheral blood, bone marrow, spleen cells, or umbilical cord blood.
- dendritic cells from these tissues and organs can be isolated by using a cell sorter or the like as an indicator of expression of dendritic cell-specific surface antigens such as CD1a. Isolation of a specific cell population using a cell sorter may be performed by a known method.
- the monocytes for obtaining the regulatory dendritic cells of the present invention may be derived from mammals, such as primates, rodents, carnivores, cloven-hoofers, and territorials, such as humans, monkeys, mice, rats, Examples include rabbits, cats, cows, dogs, horses, goats and the like, most preferably humans. Among the above, preferably, it is derived from the same species as the animal to be prevented or treated for diseases by the regulatory dendritic cells of the present invention.
- Monocytes and dendritic cells can be cultured by well-known lymphatic cell culture techniques.
- As the culture solution for example, RPMI1640 or DMEM can be used, and an appropriate antibiotic or animal serum may be added to these basic media and cultured.
- the culture vessel is not limited, and commercially available plates, dishes, and flasks can be appropriately selected and used depending on the culture scale.
- [1,2,4] Triazolo [1,5-a] pyrimidine derivatives used in the present invention are specifically compounds described in JP-A-2005-154335 and International Publication No. 2004/108729. It is. That is, the [1,2,4] triazolo [1,5-a] pyrimidine derivative used in the present invention is preferably a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof. .
- Ar represents an optionally substituted aromatic hydrocarbon group or an aromatic heterocyclic group containing 1 to 4 heteroatoms
- X represents O, S, NH, N— CH 3 or N—CN
- Y represents a phenyl group or RNH group which may have a substituent
- R represents a hydrogen atom, a cyano group or a linear or branched chain which may have a substituent Or 1 to 4 heteroatoms independently selected from a cyclic alkyl group, an optionally substituted aromatic hydrocarbon group, or an optionally substituted N, O and S
- the phenyl group or the aromatic heterocyclic group is a halogeno group, a hydroxyl group, a cyano group, a nitro group, a (C1-C6) alkyl
- X may be O
- R may be a halogeno group, a hydroxyl group, a (C1 to C6) alkyl group, (C1 -C6) alkoxyl group, (C1-C7) phenyl optionally substituted with 1 to 3 different or identical groups selected from the substituent group consisting of acyloxy group, trifluoromethyl group and trifluoromethoxy group Group or general formula (2)
- R1 represents a hydrogen atom or a (C1-C6) alkyl group
- R2 represents a hydrogen atom or a methyl group
- R3 represents a hydrogen atom
- a phenyl group (the phenyl group is a halogeno group, a hydroxyl group, (C1-C6 )
- An alkyl group and (C1-C6) which may be substituted with one group selected from the group consisting of alkoxyl groups) or (C1-C10) alkyl groups (the alkyl group is a halogeno group, a hydroxyl group, (C1 To C6) an alkoxyl group, (C1 to C7) optionally substituted by the same or different 1 or 2 groups selected from the group consisting of an acyloxy group and a trifluoromethyl group ⁇ 2,4] triazolo [1, 5-a] pyrimidin-2-ylurea derivative, or a pharmaceutically acceptable salt thereof.
- [1,2,4] triazolo [1,5-a] pyrimidine derivative used in the present invention include the following compounds, but are not limited thereto.
- the most preferred specific example of the [1,2,4] triazolo [1,5-a] pyrimidine derivative used in the present invention is (S)-(+)-1- (5-hydroxy-1,5-dimethylhexyl). -3- [7- (4-methoxyphenyl)-[1,2,4] triazolo [1,5- ⁇ ] pyrimidin-2-yl] urea.
- the concentration of the [1,2,4] triazolo [1,5-a] pyrimidine derivative used for the culture is 1 ng / mL to 5000 ng / mL, preferably 10 ng / mL to 500 ng / mL.
- the concentrations of GM-CSF, IL-4, IL-10, TGF- ⁇ , TNF- ⁇ , and LPS are 1 ng / mL to 1000 ng / mL, preferably 10 ng / mL to 100 ng / mL.
- the number of culture days required for stimulation is not limited.
- monocytes can be combined with [1,2,4] triazolo [1,5-a] pyrimidine derivatives, cytokines and / or inflammatory stimuli for several to 10 days. What is necessary is just to culture
- the culture period during which cells with the desired degree of differentiation can be obtained can be determined as appropriate.
- Conditions such as the concentration of [1,2,4] triazolo [1,5-a] pyrimidine derivative, cytokines and / or inflammatory stimuli used for stimulation, and the duration of stimulation are the antigen unresponsiveness of foreign CD4-positive T cells.
- the dendritic cell phenotype can be determined as indicators.
- the regulatory dendritic cell of the present invention is stimulated with an antigen related to the disease to be treated.
- an antigen if it is an autoimmune disease or an allergic disease, an antigen protein or peptide present in a tissue / organ associated with the disease, or RNA, DNA, or a variant thereof encoding the same is used.
- dendritic cells endogenously express foreign antigens and do not need to be reapplied.
- donor- or recipient-derived antigens may be used. It is possible.
- the regulatory dendritic cells of the present invention may be cultured together with the antigen in vitro.
- the period is from 10 days to 1 day including the last day of culture.
- 1 ng / ml to 10 mg / ml, preferably 10 ng / ml Apply in vitro at a concentration of 5 mg / ml.
- the antigen is usually given simultaneously with or before the inflammatory stimulus.
- the regulatory dendritic cells of the present invention can be used for therapeutic and prophylactic agents for immune diseases caused by immune abnormalities.
- immune diseases include transplant rejection, autoimmune diseases, allergic diseases, inflammatory diseases, sepsis, shock and the like.
- transplant rejection examples include acute rejection in transplant, graft-versus-host disease, and chronic rejection.
- the regulatory dendritic cells of the present invention can be used for induction of immune tolerance, in addition to treatment and prevention of transplant rejection.
- the transplanted organ can be any organ such as bone marrow, kidney, liver, heart and pancreas.
- the relationship between donor hosts is possible in any case such as transplantation between different species, transplantation between different strains, transplantation between blood incompatibility and the like.
- the regulatory dendritic cells of the present invention are immunosuppressive for organ transplantation such as bone marrow transplantation, peripheral blood stem cell transplantation, and cord blood stem cell transplantation used in cancer treatment, autoimmune disease treatment, gene therapy, regenerative medicine and the like. It can also be used for the purpose of long-term engraftment of transplanted organs.
- Rheumatoid arthritis multiple sclerosis, systemic lupus erythematosus, Sjogren's syndrome, Crohn's disease, ulcerative colitis, idiopathic thrombocytopenia, aplastic anemia, autoimmune hepatitis, letters Trans-autoimmune myocarditis, idiopathic thrombocytopenia purpura, Behcet's disease, autoimmune gastritis, insulin-dependent diabetes mellitus, myasthenia gravis, polymyositis, scleroderma, mixed connective tissue disease, ankylosing spine Inflammation, chronic thyroiditis, pemphigus, Guillain-Barre syndrome, HTLV-1-related myelopathy and the like.
- Inflammatory diseases include polyarteritis, sarcoidosis, glomerulonephritis, nephrotic syndrome, refractory vasculitis, Wegener's syndrome and the like.
- the dose of the regulatory dendritic cell of the present invention is appropriately set to a dose at which a desired effect is observed in the administration subject. Specifically, about 0.5 ⁇ 10 5 to 10 9 regulatory dendritic cells of the present invention are administered intravenously, subcutaneously or intradermally (preferably intravenously) to the administration subject (individual). Is done.
- the medium for administration is not particularly limited as long as it is a medium that does not give side effects to the administration subject and does not impair the function of the regulatory dendritic cells of the present invention, and may be usually used. Examples thereof include culture media such as RPMI 1640 and DMEM, Hank's buffer, phosphate buffered saline (PBS), physiological saline, and glucose solution.
- the administration target is not particularly limited as long as it is a mammal.
- it is a human.
- the timing of administration of preventive or therapeutic agents for various diseases to the administration subject is not particularly limited and can be performed as needed.
- administration prior to treatment for which onset is expected is preferable.
- the administration time and dose of human immunoregulatory dendritic cells can be appropriately determined according to the type of disease, the severity of the disease, the condition of the patient, and the like.
- the present invention also includes a pharmaceutical composition or a pharmaceutical kit containing the regulatory dendritic cells of the present invention.
- the pharmaceutical composition of the present invention is not particularly limited as long as it contains the regulatory dendritic cell of the present invention.
- the regulatory dendritic cell of the present invention gives side effects to the administration subject as described above. And those suspended in a medium that does not impair the function of the regulatory dendritic cells of the present invention.
- the pharmaceutical kit of the present invention refers to a combination of the regulatory dendritic cells of the present invention or the pharmaceutical composition of the present invention and other drugs.
- the other drugs are not limited as long as they are known for the treatment and prevention of immune diseases caused by abnormal immunity.
- immune diseases caused by abnormal immunity.
- Immunomodulators such as Actarit, Robenzalid, methotrexate, leflunomide, tacrolimus, mizoribine, cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, and other immunosuppressants, infliximab, etanercept, adalimumab, tocilizumab, etc.
- NSAIDs such as mefenamic acid, mefenamic acid, diclofenac sodium, nabumetone, etodolac, loxoprofen sodium, meloxicam, prednisolone, methylprednisolone, methylprednisolone Steroid drugs such as acetate ester, methylprednisolone succinate sodium, dexamethasone, betamethasone, hydrocortisone, zidovudine, lamivudine, abacavir, emtricitabine and other NRTIs, nucleotide reverse transcriptase inhibitors such as tenofovir, NNRTIs such as efavirenz, atazanavir, Examples include protease inhibitors such as amprenavir, lovinavir, ritonavir, darunavir, and integrase inhibitors such as raltegravir.
- the regulatory dendritic cells of the present invention will be described with reference to some embodiments. However, the present invention is not limited to these examples.
- C57BL / 6 mouse bone marrow cells were derived from 20 ng / mL GM-CSF (Peprotech, derived: rabbit) and 20 ng / mL IL-4 (Peprotech, derived). : Rabbit) was cultured in 10% FCS-RPMI1640 medium for 7 days to differentiate into dendritic cells, and then 20 ng / mL TNF- ⁇ (Peprotech, derived: rabbit) was added to mature.
- NK026680 treatment was performed by adding 50 ng / mL on the second and fourth days of culture and 250 ng / mL on the sixth day.
- C57BL / 6 mice Spleens were removed from C57BL / 6 mice (SLC, male, 10-12 weeks old), and spleen cells were removed from the spleen in RPMI 1640 medium and single using a 26G syringe.
- C57BL / 6 mouse spleen cells were obtained by cell transformation.
- C57BL / 6 mouse T cells were isolated and collected from C57BL / 6 mouse spleen cells using nylon wool (R & D systems).
- C57BL / 6 mouse spleen cell extract C57BL / 6 mouse spleen cells were pulverized with an ultrasonic grinder and frozen at ⁇ 80 ° C. Thereafter, thawing was performed, cell debris was removed by centrifugation (300 g, 5 minutes), and the supernatant was used as an extract.
- C3He / J mouse bone marrow cells were cultured in 10% FCS-RPMI1640 medium containing 20 ng / mL GM-CSF and 20 ng / mL IL-4 for 7 days. Differentiated into dendritic cells.
- NK026680 treatment was performed by adding 50 ng / mL on the 2nd and 4th days of culture and 250 ng / mL on the 6th day. On the 6th day, C57BL / 6 mouse spleen cell extract was also added.
- BALB / c mouse spleen cell extract The spleen is removed from BALB / c mice (SLC, male, 10-12 weeks old), and the spleen cells are removed from the spleen in RPMI1640 medium and made into single cells using a 26G syringe. BALB / c mouse spleen cells were obtained. The spleen cells were shattered with an ultrasonic grinder and frozen at ⁇ 80 ° C. Thereafter, thawed cells were removed by centrifugation (300 g, 5 minutes), and the supernatant was used as an extract.
- Example 1 BALB / c mouse-derived spleen cell extract was added to bone marrow cell-derived dendritic cells collected from C57BL / 6 mice to present BALB / c antigen.
- the BALB / c antigen uptake effect was confirmed by measuring the expression of BALB / c major histocompatibility antigen (MHC) I-Ad (antibody: BD pharmingen) by flow cytometry. At this time, the cells were cultured in the presence or absence of NK026680 and then matured with TNF- ⁇ (Peprotech, origin: rabbit). Maturation of dendritic cells was confirmed by analysis of expression of mature dendritic cell markers by flow cytometry).
- MHC major histocompatibility antigen
- NK-DC NK026680-treated dendritic cells
- CTR-DC untreated dendritic cells
- Example 1 The results of Example 1 are shown in Table 1.
- MFI which is the binding amount of fluorescently labeled antibodies of CD40, CD80, and CD86
- the expression levels of CD40, CD80, and CD86 of NK026680-treated dendritic cells (NK-DC) of the present invention are untreated dendritic cells ( Less than CTR-DC).
- Low expression of costimulatory molecules is a property of regulatory dendritic cells, indicating that NK026680-treated dendritic cells of the present invention are regulatory dendritic cells.
- Example 2 The results of Example 2 are shown in Table 2.
- the concentrations of IL-6 and IL-12p40 contained in the culture supernatant of NK026680-treated dendritic cells were lower than that of untreated dendritic cells.
- Low production of the immune response stimulating cytokines IL-6 and IL-12p40 is a property of regulatory dendritic cells, indicating that the NK026680-treated dendritic cells of the present invention are regulatory dendritic cells.
- Example 3 In this Example 3, as in Example 1, NK026680 treatment (NK-DC), which is a regulatory dendritic cell of the present invention differentiated and matured from C57BL / 6 mouse bone marrow cells, and untreated dendritic cells (CTR) -DC) was obtained. Further, after differentiation from C57BL / 6 mouse bone marrow cells into dendritic cells, BALB / c antigen was presented in the same manner as in Example 1, but immature dendritic cells that had not been matured by TNF- ⁇ (unstim- DC) was also obtained. After these C57BL / 6 mouse T cells were mixed with these three dendritic cells, the uptake of 3H-TdR (GE healthcare) was measured. The amount of 3H-TdR uptake indicates the ability of T cells to induce activation of dendritic cells against foreign antigens.
- NK026680 treatment which is a regulatory dendritic cell of the present invention differentiated and matured from C57BL / 6 mouse bone
- Example 3 The results of Example 3 are shown in FIG. NK-DC was less capable of inducing T cell activation against BALB / c antigen than CTR-DC. Further, the ability of NK-DC to induce T cell activation was equivalent to that of unstim-DC. That is, it was shown that NK-DC has a T cell-inducing activity reduced to the same extent as that of immature dendritic cells even when stimulated with a foreign antigen.
- Example 4 In Example 4, a C57BL / 6 mouse spleen cell extract was added to dendritic cells derived from C3He / J mouse bone marrow cells to present C57BL / 6 antigen. The C57BL / 6 antigen uptake effect was confirmed by measuring the expression of BALB / c MHC I-Ab (antibody: BD farmingen) by flow cytometry. At this time, the cells were cultured in the presence or absence of NK026680.
- BALB / c MHC I-Ab antibody: BD farmingen
- NK026680-treated (NK-DC) and untreated dendritic cells (CTR-DC) were intravenously administered and transferred to C3He / J mice (SLC, male, 10-12 weeks old) (dose number 3 ⁇ 10 6 / animal, medium: phosphate buffered saline (PBS)).
- PBS phosphate buffered saline
- Example 4 The results of Example 4 are shown in FIG. In the NK-DC transfer group, the survival rate and the survival period were significantly improved as compared with the CTR-DC transfer group and the No-treat group.
- the method for producing regulatory dendritic cells according to the present invention a large amount of regulatory dendritic cells can be obtained in a simple manner. Moreover, the regulatory dendritic cells produced by the method for producing regulatory dendritic cells of the present invention are useful for the prevention and treatment of diseases caused by immune abnormalities and excessive responses.
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Abstract
Description
(1) 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の存在下で培養することを含む、制御性樹状細胞の作製方法。
(2) [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体が、(S)-(+)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレアである、(1)に記載の制御性樹状細胞の作製方法。
(3) 制御性樹状細胞に誘導可能な細胞が、樹状細胞又はその前駆細胞である、(1)又は(2)に記載の制御性樹状細胞の作製方法。
(4) 樹状細胞の前駆細胞が、単球である、(3)に記載の制御性樹状細胞の作製方法。
(6) 細胞をGM-CSF及びIL-4の存在下で培養することを含む、(1)から(5)の何れか1項に記載の制御性樹状細胞の作製方法。
(7) 細胞をTNF-α及び/またはLPSの存在下で培養することを含む、(1)から(6)のいずれか1項に記載の制御性樹状細胞の作製方法。
(9) 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の非存在下で培養することにより得られる細胞と比較して、CD40、CD80及びCD86の発現量が低い、(8)に記載の制御性樹状細胞。
(10) 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の非存在下で培養することにより得られる細胞と比較して、IL-6及びIL-12p40の産生量が低い、(8)又は(9)に記載の制御性樹状細胞。
(11) 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の非存在下で培養することにより得られる細胞と比較して、異系抗原に対するT細胞の活性化誘導能が低い、(8)から(10)の何れか1項に記載の制御性樹状細胞。
(13) 免疫系の異常応答及び過剰応答に起因する移植拒絶反応、移植片対宿主病、自己免疫疾患、アレルギー疾患、慢性炎症性疾患及び敗血症の予防及び/又は治療のために使用する、(12)に記載の医薬組成物又は医薬キット。
(15) [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体が、(S)-(+)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレアである、(14)に記載の使用。
(17) [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体が、(S)-(+)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレアである、(16)に記載の制御性樹状細胞誘導試薬。
具体的には例えば、Arは置換基を有していてもよいフェニル基若しくは置換基を有していてもよいN、O及びSから選択される1個のヘテロ原子を含有する5~6員の芳香族複素環基であり、該フェニル基若しくは該芳香族複素環基はハロゲノ基、水酸基、シアノ基、ニトロ基、(C1~C6)アルキル基、(C1~C6)アルコキシル基及びアルキレンジオキシ基からなる置換基群より選ばれる同一又は異なった1又は2個の基で置換されていてもよく、XはOであり、Rはハロゲノ基、水酸基、(C1~C6)アルキル基、(C1~C6)アルコキシル基、(C1~C7)アシルオキシ基、トリフルオロメチル基及びトリフルオロメトキシ基からなる置換基群より選ばれる同一又は異なった1~3個の基で置換されていてもよいフェニル基又は
一般式(2)
(S)-1-(3-エトキシ-1-メチルプロピル)-3-[7-(3,4-メチレンジオキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
(S)-1-(4-メトキシ-1-メチルブチル)-3-[7-(4-メトキシフェニル-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
(S)-1-(4-ヒドロキシ-1,4-ジメチルペンチル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
(S)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
(S)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-{7-[3-(ピリジン-3-イルメトキシ)フェニル]-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル}ウレア,
(S)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-(7-チオフェン-2-イル[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル)ウレア,
(S)-1-[1-(3-メトキシフェニル)エチル]-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
(S)-1-[7-(3,4-メチレンジオキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]-3-[1-(3-メトキシフェニル)エチル]ウレア,
(S)-1-[7-(3,4-メチレンジオキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]-3-[1-(3,4,5-トリメトキシフェニル)エチル]ウレア,
(S)-1-(7-チオフェン-2-イル[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル)-3-[1-(3,4,5-トリメトキシフェニル)エチル]ウレア,
(S)-1-[1-(3,4-メチレンジオキシフェニル)エチル]-3-{7-[3-(ピリジン-3-イルメトキシ)フェニル]-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル}ウレア,
(S)-1-(1,5-ジメチルヘキシル)-3-[7-(4-ヒドロキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
(S)-1-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]-3-(1-フェニルエチル)ウレア,
4-クロロ-2-メトキシ-N-(7-チオフェン-2-イル[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル)ベンズアミド,
(S)-1-(1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]ウレア,
1-(2-メトキシフェニル)-3-(7-チオフェン-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル)ウレア,
1-イソプロピル-3-(7-チオフェン-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル)ウレア,
(R)-1-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-a]ピリミジン-2-イル]-3-(1-フェニルエチル)ウレア又は
(R)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレア
C57BL/6マウス(SLC、雄、10~12週齢)から大腿骨を取り出し、RPMI1640培地中で大腿骨の両端を切断して骨内部にある骨髄組織を取り出した。26Gシリンジを用いて、この骨髄組織を単一細胞化して、C57BL/6マウス骨髄細胞を得た。
C57BL/6マウス骨髄細胞は、20ng/mLのGM-CSF(Peprotech、由来:ラビット)及び20ng/mLのIL-4(Peprotech、由来:ラビット)を含む10%FCS-RPMI1640培地で7日間培養して樹状細胞に分化させ、その後20ng/mLのTNF-α(Peprotech、由来:ラビット)を添加して成熟させた。NK026680処理は、培養2日目及び4日目に50ng/mL、6日目に250ng/mLを添加して行った。
C57BL/6マウス(SLC、雄、10~12週齢)から脾臓を取り出し、脾臓内から脾臓細胞をRPMI1640培地中で取り出し、26Gシリンジを用いて単一細胞化してC57BL/6マウス脾臓細胞を得た。C57BL/6マウスT細胞は、C57BL/6マウス脾臓細胞からナイロンウール(R&D systems)を用いて分離採取した。
C57BL/6マウス脾臓細胞を超音波粉砕器で粉々にし、-80℃に凍結させた。その後解凍し、遠心(300g・5分)にて細胞破片を除去し、その上清を抽出液とした。
C3He/Jマウス(SLC、雄、10~12週齢)から大腿骨を取り出し、RPMI1640培地中で大腿骨の両端を切断して骨内部にある骨髄組織を取り出した。26Gシリンジを用いて、この骨髄組織を単一細胞化してC3He/Jマウス骨髄細胞を得た。
C3He/Jマウス骨髄細胞は、20ng/mLのGM-CSF及び20ng/mLのIL-4を含む10%FCS-RPMI1640培地で7日間培養して樹状細胞に分化させた。NK026680処理は、培養2日目及び4日目に50ng/mL、6日目に250ng/mLを添加して行った。また、6日目に、C57BL/6マウス脾細胞抽出液も加えた。
BALB/cマウス(SLC、雄、10~12週齢)から脾臓を取り出し、脾臓内から脾臓細胞をRPMI1640培地中で取り出し、26Gシリンジを用いて単一細胞化してBALB/cマウス脾臓細胞を得た。この脾臓細胞を超音波粉砕器で粉々にし、-80℃に凍結させた。その後解凍し,遠心(300g・5分)にて細胞破片を除去し、その上清を抽出液とした。
C57BL/6マウスから採取した骨髄細胞由来の樹状細胞にBALB/cマウス由来の脾臓細胞抽出液を加えてBALB/c抗原を提示させた。BALB/c抗原取込効果は、BALB/cの主要組織適合性抗原(MHC)であるI-Ad(抗体:BD pharmingen)の発現をフローサイトメトリーで測定することで確認した.この際、NK026680の存在下、非存在下で培養した後、TNF-α(Peprotech、由来:ラビット)で成熟させた。フローサイトメトリーによる成熟樹状細胞マーカー発現解析により、樹状細胞の成熟を確認した)。本発明のNK026680処理樹状細胞(NK-DC)と未処理の樹状細胞(CTR-DC)における共刺激分子CD40、CD80及びCD86の蛍光標識抗体を反応させ、フローサイトメトリーで平均蛍光強度(MFI)を測定することによりCD40、CD80及びCD86の発現量を比較した。
本実施例2では、実施例1と同様にC57BL/6マウス骨髄細胞から分化成熟させた本発明のNK026680処理樹状細胞と未処理の樹状細胞を得た。TNF刺激後24時間培養して得た培養上清を採取し,免疫応答刺激サイトカインIL-6及びIL-12p40濃度をELISA(BD bioscience)で測定した(n=3)。
本実施例3では、実施例1と同様に、C57BL/6マウス骨髄細胞から分化成熟させた本発明の制御性樹状細胞であるNK026680処理(NK-DC)と未処理の樹状細胞(CTR-DC)を得た。また、C57BL/6マウス骨髄細胞から樹状細胞に分化させた後実施例1と同様にBALB/c抗原を提示させたが、TNF-αによる成熟を行わなかった未成熟樹状細胞(unstim-DC)も得た。これら3種の樹状細胞に対して、それぞれC57BL/6マウスT細胞を混合した後、3H-TdR(GEヘルスケア)の取り込みを測定した。3H-TdRの取り込み量は、樹状細胞の異系抗原に対するT細胞の活性化誘導能を示す。
本実施例4では、C3He/Jマウス骨髄細胞由来の樹状細胞にC57BL/6マウス脾臓細胞の抽出液を加えてC57BL/6抗原を提示させた。C57BL/6抗原取込効果は、BALB/cのMHCであるI-Ab(抗体:BD pharmingen)の発現をフローサイトメトリーで測定することで確認した.この際、NK026680の存在下、非存在下で培養した。NK026680処理(NK-DC)と未処理の樹状細胞(CTR-DC)をそれぞれC3He/Jマウス(SLC、雄、10~12週齢)に静脈内投与して移入した(投与数 3×106個/匹、媒体:燐酸緩衝塩液(PBS))。この際、樹状細胞を移入しない群(No-treat)も準備した(n=6)。7日後に、NK-DC移入群、CTR-DC移入群及びNo-treat群に、C57BL/6マウス(SLC、雄、10~12週齢)の心臓を移植して3群の生存率を比較した。
Claims (17)
- 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の存在下で培養することを含む、制御性樹状細胞の作製方法。
- [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体が、(S)-(+)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレアである、請求項1に記載の制御性樹状細胞の作製方法。
- 制御性樹状細胞に誘導可能な細胞が、樹状細胞又はその前駆細胞である、請求項1又は2に記載の制御性樹状細胞の作製方法。
- 樹状細胞の前駆細胞が、単球である、請求項3に記載の制御性樹状細胞の作製方法。
- 制御性樹状細胞に誘導可能な細胞が、末梢血、骨髄、脾臓、又は臍帯血に由来する細胞である、請求項1から4の何れか1項に記載の制御性樹状細胞の作製方法。
- 細胞をGM-CSF及びIL-4の存在下で培養することを含む、請求項1から5の何れか1項に記載の制御性樹状細胞の作製方法。
- 細胞をTNF-α及び/またはLPSの存在下で培養することを含む、請求項1から6のいずれか1項に記載の制御性樹状細胞の作製方法。
- 請求項1から7の何れか1項に記載の作製方法で作製された制御性樹状細胞。
- 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の非存在下で培養することにより得られる細胞と比較して、CD40、CD80及びCD86の発現量が低い、請求項8に記載の制御性樹状細胞。
- 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の非存在下で培養することにより得られる細胞と比較して、IL-6及びIL-12p40の産生量が低い、請求項8又は9に記載の制御性樹状細胞。
- 制御性樹状細胞に誘導可能な細胞を[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の非存在下で培養することにより得られる細胞と比較して、異系抗原に対するT細胞の活性化誘導能が低い、請求項8から10の何れか1項に記載の制御性樹状細胞。
- 請求項8から11の何れか1項に記載の制御性樹状細胞を含む医薬組成物又は医薬キット。
- 免疫系の異常応答及び過剰応答に起因する移植拒絶反応、自己免疫疾患、アレルギー疾患、炎症性疾患、敗血症又はショックの予防及び/又は治療のために使用する、請求項12に記載の医薬組成物又は医薬キット。
- 制御性樹状細胞の作製のための、[1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体の使用。
- [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体が、(S)-(+)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレアである、請求項14に記載の使用。
- [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体を含む、制御性樹状細胞誘導試薬。
- [1,2,4]トリアゾロ[1,5-a]ピリミジン誘導体が、(S)-(+)-1-(5-ヒドロキシ-1,5-ジメチルヘキシル)-3-[7-(4-メトキシフェニル)-[1,2,4]トリアゾロ[1,5-α]ピリミジン-2-イル]ウレアである、請求項16に記載の制御性樹状細胞誘導試薬。
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CN2011800105135A CN102834506A (zh) | 2010-02-23 | 2011-02-23 | 调节性树突细胞的制备方法 |
JP2012501802A JP5782426B2 (ja) | 2010-02-23 | 2011-02-23 | 制御性樹状細胞の作製方法 |
AU2011221314A AU2011221314B2 (en) | 2010-02-23 | 2011-02-23 | Method for preparing regulatory dendritic cells |
US13/580,496 US20130052734A1 (en) | 2010-02-23 | 2011-02-23 | Method for preparing regulatory dendritic cells |
CA2790922A CA2790922A1 (en) | 2010-02-23 | 2011-02-23 | Method for preparing regulatory dentritic cells |
KR1020127024621A KR20120135265A (ko) | 2010-02-23 | 2011-02-23 | 제어성 수상세포의 작제방법 |
EP11747355.3A EP2540821A4 (en) | 2010-02-23 | 2011-02-23 | METHOD FOR THE PRODUCTION OF REGULATORY DENDRITIC CELLS |
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WO2014010206A1 (ja) * | 2012-07-13 | 2014-01-16 | Sbiファーマ株式会社 | 免疫寛容誘導剤 |
US9314443B2 (en) | 2011-10-12 | 2016-04-19 | National Center For Child Health And Development | Enhancer of survival of transplanted organ |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004108729A (ja) | 2002-09-20 | 2004-04-08 | Zexel Valeo Climate Control Corp | 両タンク型熱交換器及びその組付方法 |
JP2004298181A (ja) | 2003-03-18 | 2004-10-28 | Kirin Brewery Co Ltd | 免疫制御性樹状細胞の調製法およびその用途 |
WO2004108729A1 (ja) | 2003-06-03 | 2004-12-16 | Nippon Kayaku Kabushiki Kaisha | [1,2,4]トリアゾロ[1,5−a]ピリミジン−2−イルウレア誘導体とその用途 |
JP2005139119A (ja) * | 2003-11-07 | 2005-06-02 | Nippon Kayaku Co Ltd | 新規な尿素誘導体の製造法およびその中間体 |
JP2005154335A (ja) | 2003-11-25 | 2005-06-16 | Nippon Kayaku Co Ltd | [1,2,4]トリアゾロ[1,5−a]ピリミジン誘導体の新規医薬用途 |
JP2006290761A (ja) | 2005-04-07 | 2006-10-26 | Institute Of Physical & Chemical Research | 炎症性疾患の予防又は治療剤 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1674454A4 (en) * | 2003-10-17 | 2006-12-27 | Nippon Kayaku Kk | SUBSTITUTED 2-AMINO-1,2,4-TRIAZOLO 1,5-A-PYRIMIDINE DERIVATIVE AND THE USE THEREOF |
-
2011
- 2011-02-23 AU AU2011221314A patent/AU2011221314B2/en not_active Ceased
- 2011-02-23 WO PCT/JP2011/053906 patent/WO2011105394A1/ja active Application Filing
- 2011-02-23 CA CA2790922A patent/CA2790922A1/en not_active Abandoned
- 2011-02-23 US US13/580,496 patent/US20130052734A1/en not_active Abandoned
- 2011-02-23 CN CN2011800105135A patent/CN102834506A/zh active Pending
- 2011-02-23 RU RU2012140456/10A patent/RU2597976C2/ru not_active IP Right Cessation
- 2011-02-23 EP EP11747355.3A patent/EP2540821A4/en not_active Withdrawn
- 2011-02-23 JP JP2012501802A patent/JP5782426B2/ja active Active
- 2011-02-23 KR KR1020127024621A patent/KR20120135265A/ko not_active Application Discontinuation
-
2015
- 2015-01-28 US US14/607,105 patent/US20150139971A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004108729A (ja) | 2002-09-20 | 2004-04-08 | Zexel Valeo Climate Control Corp | 両タンク型熱交換器及びその組付方法 |
JP2004298181A (ja) | 2003-03-18 | 2004-10-28 | Kirin Brewery Co Ltd | 免疫制御性樹状細胞の調製法およびその用途 |
WO2004108729A1 (ja) | 2003-06-03 | 2004-12-16 | Nippon Kayaku Kabushiki Kaisha | [1,2,4]トリアゾロ[1,5−a]ピリミジン−2−イルウレア誘導体とその用途 |
JP2005139119A (ja) * | 2003-11-07 | 2005-06-02 | Nippon Kayaku Co Ltd | 新規な尿素誘導体の製造法およびその中間体 |
JP2005154335A (ja) | 2003-11-25 | 2005-06-16 | Nippon Kayaku Co Ltd | [1,2,4]トリアゾロ[1,5−a]ピリミジン誘導体の新規医薬用途 |
JP2006290761A (ja) | 2005-04-07 | 2006-10-26 | Institute Of Physical & Chemical Research | 炎症性疾患の予防又は治療剤 |
Non-Patent Citations (14)
Title |
---|
FUJITA S; SEINO K; SATO K; SATO Y; EIZUMI K; YAMASHITA N; TANIGUCHI M; SATO K.: "Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response", BLOOD, vol. 107, no. 9, 2006, pages 3656 - 3664 |
FUJITA S; YAMASHITA N; ISHII Y; SATO Y; SATO K; EIZUMI K; FUKAYA T; NOZAWA R; TAKAMOTO Y; YAMASHITA N: "Regulatory dendritic cells protect against allergic airway inflammation in a murine athmatic model", J ALLERGY CLIN IMMUNOL, vol. 121, no. 1, 2008, pages 95 - 104 |
HARA Y ET AL.: "A novel chemical compound, NK026680, targets dendritic cells to prolong recipient survival after rat liver grafting.", TRANSPLANTATION, vol. 84, no. 3, 2007, pages 407 - 414, XP009170970 * |
SAIGA K ET AL.: "NK026680, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft- versus-host reaction in mice.", BONE MARROW TRANSPLANTATION, vol. 37, 2006, pages 317 - 323 * |
SAIGA K ET AL.: "NK026880, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft- versus-host reaction in mice.", PROCEEDINGS OF THE JAPANESE SOCIETY FOR IMMUNOLOGY, vol. 36, 2006, pages 65, XP008168635 * |
SAIGA K; TOYODA E; TOKUNAKA K; MASUDA A; MATSUMOTO S; MASHIBA H; KURAMOCHI H; NEMOTO K; ABE F; KAWAGISHI N: "NK026680, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft-versus-host reaction in mice", BONE MARROW TRANSPLANT, vol. 37, no. 3, 2006, pages 317 - 323 |
SAIGA K; YOSHIDA M; NAKAMURA I; TOYODA E; TOKUNAKA K; MOROHASHI H; ABE F; NEMOTO K; NOSE M.: "Evaluation of the ameliorative effects of immunosuppressants on crescentic glomerulonephritis in SCG/Kj mice", INT IMMUNOPHARMACOL, vol. 8, no. 9, 2008, pages 1183 - 1189, XP022819480, DOI: doi:10.1016/j.intimp.2008.04.005 |
SATO K; YAMASHITA N; BABA M; MATSUYAMA T.: "Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells", BLOOD, vol. 101, no. 9, 2003, pages 3581 - 3589 |
SATO K; YAMASHITA N; YAMASHITA N; BABA M; MATSUYAMA T.: "Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse", IMMUNITY, vol. 18, no. 3, 2003, pages 367 - 379, XP002338253 |
See also references of EP2540821A4 |
SUSUMU SHIBASAKI ET AL.: "NK026680 o Mochiita Regulatory DC ni yoru Men'eki Yokusei Koka no Kento", JOURNAL OF JAPAN SURGICAL SOCIETY, vol. 111, no. ISS.2, 5 March 2010 (2010-03-05), pages 477 * |
SUSUMU SHIBASAKI ET AL.: "Shinki Kagobutsu NK026680 o Mochiita ex-vivo Yudo Seigyosei Jujo Saibo no Men'eki Yokusei Koka", JAPANESE JOURNAL OF TRANSPLANTATION, vol. 45, October 2010 (2010-10-01), pages 179 * |
TAKESHI AOYAGI ET AL.: "Shinki NF-KB Sogaiyaku DHMEQ ni yoru Men'eki Yokusei-sei Jujo Saibo no Yudo", THE JOURNAL OF THE JAPANESE SOCIETY OF LYMPHORETICULAR TISSUE, vol. 48, 2008, pages 103 * |
YOSHIAKI HARA ET AL.: "Shinki Men'eki Yokusei Kagobutsu NK026680: sono Jujo Saibo o Kaishita Men'eki Yokusei Mechanism no Kento", JOURNAL OF JAPAN SURGICAL SOCIETY, vol. 108, no. ISS.2, 2007, pages 708 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US9314443B2 (en) | 2011-10-12 | 2016-04-19 | National Center For Child Health And Development | Enhancer of survival of transplanted organ |
US9901558B2 (en) | 2011-10-12 | 2018-02-27 | National Center For Child Health And Development | Enhancer of survival of transplanted organ |
US9937138B2 (en) | 2011-10-12 | 2018-04-10 | National Center For Child Health And Development | Enhancer of survival of transplanted organ |
WO2014010206A1 (ja) * | 2012-07-13 | 2014-01-16 | Sbiファーマ株式会社 | 免疫寛容誘導剤 |
JP5904518B2 (ja) * | 2012-07-13 | 2016-04-13 | Sbiファーマ株式会社 | 免疫寛容誘導剤 |
US9399029B2 (en) | 2012-07-13 | 2016-07-26 | Sbi Pharmaceuticals Co., Ltd. | Immune tolerance inducer |
Also Published As
Publication number | Publication date |
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US20150139971A1 (en) | 2015-05-21 |
JPWO2011105394A1 (ja) | 2013-06-20 |
RU2012140456A (ru) | 2014-03-27 |
CA2790922A1 (en) | 2011-09-01 |
KR20120135265A (ko) | 2012-12-12 |
JP5782426B2 (ja) | 2015-09-24 |
RU2597976C2 (ru) | 2016-09-20 |
EP2540821A1 (en) | 2013-01-02 |
CN102834506A (zh) | 2012-12-19 |
AU2011221314B2 (en) | 2015-05-14 |
EP2540821A4 (en) | 2013-08-14 |
US20130052734A1 (en) | 2013-02-28 |
AU2011221314A1 (en) | 2012-10-11 |
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