| Project/Area Number |
15591325
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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 |
General surgery
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| Research Institution | University of Tsukuba |
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Principal Investigator |
YUZAWA Kenji University of Tsukuba, Graduate School of Comprehensive Human Sciences, Assistnat Professor, 大学院・人間総合科学研究科, 講師 (10240160)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Tsuyoshi Ajinomoto Co., Inc., Pharmaceutical Research Laboratories, Chief Investigator, 医薬研究所, 主席研究員
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | immunosuppressive drug / organ transplantation / NF-kB / APC0576 / サル |
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| Research Abstract |
APC0576 is a novel synthetic molecule with a small molecular weight and inhibits IL-1-induced NF-kB-mediated gene activation in a cell-based reporter gene assay using human endothelial cells. APC0576 is orally bioavailabe in non-human primates and is not a macrolide structure, and has no structural relationship to current drugs. Effects of APC0576 on IL-2 production and proliferative responses in human peripheral blood mononuclear cells(hPBMC) were studied under various stimuli with in vitro culture assay. Next, female rhesus monkeys were immunized with tetanus toxoid(TTx) and APC0576 was orally administered for 4 weeks. Serum specific antibody for TTx was monitored weekly using ELISA and delayed-type hypersensitivity(DTH) reaction was examined after 4 weeks of APC0576 treatment. Furthermore, APC0576 was orally administered to rhesus monkeys transplanted with allogeneic kidney for 32 days to evaluate the immunosuppressive activity. APC0576 effectively suppressed IL-2 production and proliferation in activated hPBMC. Both delayed-type hypersensitivity(DTH) reaction and specific antibody formation evoked by TTx was significantly and dose-dependently attenuated by 4 weeks treatment of APC0576 without any serious toxicological signs. Allogeneic kidneys grafted in rhesus monkeys were not rejected and were fully functioned during 32 days period of APC0576 treatment, though they were rapidly rejected after the withdrawal of the drug. A novel orally available immunosuppressive agent, APC0576, effectively inhibited T cell-based immune responses both in vitro and in vivo. APC0576 may have potential for a therapeutic agent in clinical organ transplantation and various cytokine -mediated diseases.
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