| Project/Area Number |
14570419
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内科学一般
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| Research Institution | NHO Nagasaki Medical Center |
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Principal Investigator |
MIGITA Kiyoshi NHO Nagasaki Medical Center Clinical Research Center, Department of Immunology, Director, 免疫研究部長 (60264214)
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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 |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Rheumatoid arthritis / Mitogen-activated protein kinase / p53 / leflunomide / matrixmetalloproteincese / tacrolimus / 細胞周期 / プロテアゾーム |
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| Research Abstract |
Leflunomide is an immuneregulatory drug that has shown effectiveness in the prevention of organ graft rejection as well as in an array of autoimmune diseases. In order to explore the mechanism of leflunomide-mediated immunosuppression, we investigated the effects of leflunomide on antigen-stimulated T cells in vivo. Leflunomide induced p53 expression in SEB-activated V□8^+ T cells. Also, increased levels of proliferating cell nuclear antigen (PCNA) and Cyclin E expression of SEB-activated V□8^+ T cells was suppressed by leflunomide. Our data suggest that the leflunomide-mediated cell cycle regulation of activated T cells may present a potential mechanism of immunosuppression achieved by leflunomide treatment. We also investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinases (MAPK) activation in IL-1β-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially A77 1726 efficiently suppressed IL-1β-stimulated rheumatoid synovial fibroblasts. Our results suggest that the suppression of MAPK signaling pathway and MMPs synthesis in rheumatoid synovial fibroblats is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.
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