| Project/Area Number |
01870095
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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 |
Chemical pharmacy
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| Research Institution | Kyoto University |
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Principal Investigator |
FUJITA Tetsuro Kyoto Univ., Fac. of Pharmaceutical Sci. Professor, 薬学部, 教授 (40027024)
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| Co-Investigator(Kenkyū-buntansha) |
OKUMOTO Takeki Yoshitomi Pharm. Ind. Ltd., Chief Researcher, 室長
IKUMOTO Takeshi Taito Co. Ltd., Chief Researcher, 主任研究員
IIDA Akira Kyoto Univ., Fac. of Pharm. Sci., Assistant, 薬学部, 助手 (40202816)
INOUE Kenichiro Kyoto Univ., Fac. of Pharm. Sci., Assistant, 薬学部, 助手 (40025713)
UEDA Shinichi Kyoto Univ., Fac. of Pharm. Sci., Associate Prof., 薬学部, 助教授 (20025688)
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| Project Period (FY) |
1989 – 1990
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| Project Status |
Completed (Fiscal Year 1990)
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| Budget Amount *help |
¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 1990: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1989: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Keywords | Immunosuppressant / Isaria / Fungus / Abnormal amino acid / structure elucidation / Mixed lymphocyte reaction / Immunosuppressive mechanism / structure-activity relationship / 免疫抑制剤 / 細胞傷害性T細胞 / 細胞特異抗体 / 細胞毒性 / 免疫抑制作用機序 / マイセリア属菌 / 非蛋白質アミノ酸 / 免疫抑制 / 冬虫夏草 / イサリア属菌 / アミノ酸 / マイリオシン |
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| Research Abstract |
We have found the immunosuppressive activity in the culture broth of Isaria sinclairii and then isolated an immunosuppressant, ISP-I, which was characterized as (2S, 3S, 4R)- (E) -2-amino-3, 4-dihydroxy-2-hydroxymethy1-14-oxoeicos-6-enoic acid. Immunosuppressive activities of ISP-I and the derivatives are as follows : 1) The suppressive activity on mouse allogeneic mixed lymphocyte reaction was equal to or higher than that of cyclosporin A (CsA). 2) Examination of its 13 derivatives resulted in the expression and increment of the activity attributable to the amino group at C-2, the double bond at C-6 and the carbon chain from C-8 to C-20.14-Deoxo-ISP-I was 10 times more active than ISP-I. 3) In the suppression on the mouse anti-sheep red blood cell antibody production and on the induction of allo-reactive cytotoxic T cells, 14-deoxo-ISP-I was 10 times more effective than ISP-I which was 100 times more active than CsA. 4) In the suppression on the mouse allo-reactive specific antibody production by the oral administration, ISP-I was 100 times more effective than CsA. 5) Among the 13 derivatives, ISP-I and its 14-deoxo derivative were most toxic to various human tumor cells and less than CsA. 6) CsA inhibits the production of the cytokines such as interleukin 2 (IL-2), while ISP-I suppresses the proliferation of T cells by IL-2, indicating the different mechanisms in the expression of immunosuppression.
Moreover, three ISP-I congeners were isolated from the mycelia of the highly ISP-I producing species of Mycelia sterilia and their structures were determined.
Therefore, ISP-I and the derivatives are new immunosuppressants having different mechanism from that of CsA. Their usefulness remains to be proved in practical grafting experiments.
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