| Project/Area Number |
11694294
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | KUMAMOTO UNIVERSITY |
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Principal Investigator |
NISHIMURA Yasuharu KUMAMOTO UNIV., GRAD. SCHL. MED. SCIENCES, PROFESSOR, 大学院・医学研究科, 教授 (10156119)
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| Co-Investigator(Kenkyū-buntansha) |
JUN-ICHI Kira KYUSHU UNIV., GRAD. SCHL. MED. DEPT. OF NEUROLOGY NEUROLOGICAL INST., PROFESSOR, 大学院・医学研究科, 教授 (40183305)
IRIE Atushi KUMAMOTO UNIV., GRAD. SCHL. MED. SCIENCES, RES. ASSOCIATE, 大学院・医学研究科, 助手 (30250343)
SENJU Satoru KUMAMOTO UNIV., GRAD. SCHL. MED. SCIENCES, ASSOC. PROFESSOR, 大学院・医学研究科, 講師 (50274709)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥9,770,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2001: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥3,200,000 (Direct Cost: ¥3,200,000)
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| Keywords | Autoimmune diseases / Molecular mimicry / Type I diabetes / Vogt-Koyanagi-Harada disease / Autoreactive CD4^+ T cells / Expression cloning of T cell epitopes / HLA class II / T cell response / 感染性微生物 / グルタミン酸脱炭酸酵素65 / MHCクラスII分子 / 発現クローニング / Vogt-小柳-原田病 / 虹彩毛様体炎 / HLA / SEREX / LEDGF / UACA / 多発性硬化症 / ミエリン蛋白 / HLAクラスII分子 / 自己抗原ペプチド / エピトープライブラリー |
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| Research Abstract |
In the previous studies, we discovered assedations between specific HLA class II alleles and susceptibility to autoimmune diseases, and examined binding peptide motifs of disease-associated HLA class II molecules. In this study, to clarify the mechanisms of the disease-association of specific HLA alleles, we carried out the following researches. Identification of self peptides recognized by disease-related autoreactive T cell clones. We established many auto-antigen specific CD4^+ T cell clones from Asian type multiple sclerosis (MS) and anti-phosopholipid antibody syndrome (APS) patients. We identified many epitopes derived from self antigens and restricting HLA class II molecules, and examined the cytokines produced by the T cell clones. In addition, we searched for the target autoantigen of Vogt -Koyanagi-Harada disease (VKH), an autoimmune diseas e in which inflammatory disorders occur in multiple organs containing melanocytes. By SEREX method, we identified LEDGF (Lens Epithelial
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Cel l Derived Growth Factor) and UACA (Uveal Autoantigen with Coiled coil domains and Ankyrin repeats) as candidates for the target antigen. 2) Establishment of a method to identify cross-reactive epitopes recognized by disease-related autoreactive T cells.We established an expression cloning system to identify epitopes for CD4^+ T cell clones. Using this system, we examined the pattern of epitopes cross-recognized by two CD4^+ T cell clones established from Type I diabetes patients and specific to glutamate decarboxylase 65 (GAD65). Based on this information, we identified several mimicry epitopes of microbial antigen origin. 3) Analysis of T cell response induced by analogues of agonistic epilopes.We generated series of L cell transfectants expressing complexes of HLA-DR4 (DRB1^*0406) and agonist or partial agonist peptides in various densities. Using the transfectants, we discovered that a certain partial agonist peptide, when presented in a very high density, can induce T cell response in a similar magnitude as a full agonist peptide, andthat the T cell response is not accompanied by phosphorylation of ZAP-70 and LAT. We identified unique profiles of produced cytokines, down-modulation of TCR, and intracellular signaling events associated with this unique T cell response. Less
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