| Project/Area Number |
03557103
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
KAWASAKI Toshishuke Kyoto University, Department of Biological Chemistry, Professor, 薬学部, 教授 (50025706)
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| Co-Investigator(Kenkyū-buntansha) |
佐々木 重夫 台糖株式会社, 研究所, 副主任研究員
KOZUTSUMI Y Kyoto University, Associate Professor, 薬学部, 助教授 (70205425)
ITOH N Kyoto University, Professor, 薬学部, 教授 (10110610)
INOUE K Gifu Pharmaceutical University, Professor, 教授 (40025713)
FUJITA T Kyoto University, Professor, 薬学部, 教授 (40027024)
SASAKI S Taito Company Ltd., Senior Researcher
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| Project Period (FY) |
1991 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥16,200,000 (Direct Cost: ¥16,200,000)
Fiscal Year 1993: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1992: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1991: ¥8,800,000 (Direct Cost: ¥8,800,000)
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| Keywords | Immunosuppressor / IL-2 / IL-2 receptor / T-cells / Sphingosine / Signal transduction / Tochukaso / Isaria / ISP-1 / シクロフィリン / シクロスポリンA / ペプチジルプロリルイソメラ-ゼ |
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| Research Abstract |
A potent immunosuppresive activity was found in the cultured broth of the fungus Isaria sinclairii. The metabolite, ISP-1 (myriocin=thermozymocidin) suppresed the proliferation of lymphocytes in mouse allogenic mixed lymphocyte reactin, but had no effect on the growth of human tumor cell lines. The metabolite was 10 to 100-fold more potent than cyclosporin A as an immunosuppresive agent of the immune response in vitro and in vivo, and apperas to be a cndidate for clinical application as a powerful immunosuppressant. The mode of actin of ISP-1 as an immunosuppressive agent was investigated and the results are compared with those of other immunosuppressive agents, such as cyclosporin A, FK-506 and rapamycin. ISP-1 is unique in its inability to bind to peptidyl prolyl isomerases which are receptors for cyclosporin A and FK-506. Like rapamycin, ISP-1 did not inhibit the productin of IL-2 but interfered the IL-2 dependent T cell growth. Contrary to the G1 arrest activity of rapamycin, ISP-1 did not affect the cell cycle of cultured T cells. These results suggest that ISP-1 inhibits the IL-2 receptor signaling pathway in the T cell activation process in a different way form that of rapamycin. Further studies using IL-2 dependent mouse cell line CTLL-2 indicated that ISP-1 inhibits very potently serine palmitoyltrasferase, the enzyme responsible for the biosynthesis of sphingosine from serine and palmitoyl-CoA.In parallel with this enzyme inhibition, ISP-1 exibited marked inhibitory effects on the growth of CTLL-2 cells and this inhibition was released by the addition of sphingosine in the media. These results suggest a new interesting possibility that some compounds associated with the biosynthesis of sphingosine may be involved in the IL-2 initiated signal transduction.
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