| Project/Area Number |
14370115
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 UNIVERSITY, GRAD.SCHL.MED.SCIENCES, PROFESSOR, 大学院・医学薬学研究部, 教授 (10156119)
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| Co-Investigator(Kenkyū-buntansha) |
IRIE Atsushi KUMAMOTO UNIVERSITY, GRAD.SCHL.MED.SCIENCES, RES.ASSOCIATE, 大学院・医学薬学研究部, 助手 (30250343)
SENJU Satoru KUMAMOTO UNIVERSITY, GRAD.SCHL.MED.SCIENCES, ASSOCIATE PROFESSOR, 大学院・医学薬学研究部, 助教授 (50274709)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | T cell / MHC / autoimmune diseases / epitope / intracellular signal transduction / embryonic stem cell / dendritic cell / tumor immunology / ES細胞 / TCRアンタゴニスト / T細胞シグナル伝達 / ZAP-70 / PKC / ヘルパーT細胞 / 抗原ペプチド / 抗原認識 / 交叉反応 / 分子擬態 / 自己免疫 / インバリアント鎖 / 発現クローニング |
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| Research Abstract |
Presentation of antigenic peptides by antigen presenting cells and consequent stimulation of CD4^+ T cells is crucial in the regulation of immune response. In this research project, we studied on the recognition of antigenic peptide by T cell receptor (TCR) and signal transduction pathway in CD4^+ T cells stimulated with altered peptide ligands (APL). In addition, we established a method for ES cell-based genetic engineering of dendritic cells (DC). The following results were obtained.
1)We developed an experimental system to dentify diverse T-cell epitopes from T-cell epitope-expression library, using an epitope presenting vector based on CLIP-substituted invariant chain. Using the libraries in which randomized amino acid residues were narrowed down into three successive ones, we characterized the degeneracy in the epitopes of the GAD65-reactive Th-cell clones derived from IDDM patients, and identified several microbe-derived antigens to which the Th-cell clones cross-reacted.
2)We foun
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d that a human CD4^+ T cell clone showed full proliferation in response to over-expressed partially agonistic peptide/HLA-DR4 complex. However, a protein tyrosine kinase ZAP-70, which is believed to be essential for TCR-mediated T cell activation, was not tyrosine-phosphorylated and activated. Instead, we found that other kinases B-Raf and PKCm were activated in the T cells, suggesting the presence of new signaling pathways leading to full T cell proliferation that is independent of ZAP-70 activation.
3)We established a method to generate mouse ES cell-derived DC (ES-DC). Genetic modification of ES-DC can be done by transfection of ES cells and subsequent differentiation to DC. OVA antigen-specific cytotoxic T lymphocytes were efficiently primed in vivo by injecting mice with ES-DCs introduced with an OVA-expression vector. Double-transfectant ES-DC expressing a chemokine along with OVA provided potent protection from OVA-expressing tumor cells. In addition, we demonstrated prevention of experimental autoimmune encephalomyelitis by treatment with genetically modified ES-DC. Less
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