| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Research Abstract |
NK, LAK and CTL induce cell death in tumor or virus-infected target cells by two main mechanisms. The first mechanism is direct release of cytolytic granules that contain perforin, granzymes, and granulysin by exocytosis to kill target cells. The second mechanism is mediated by the Fas ligand (Fas-L)/Fas pathway.
In the present syudy, we examined the effect that dimethyl 2,2-dichlorovinyl phosphate (DDVP), an organophosphorus pesticide has on NK, CTL and LAK activities of PKO mice in vitro using the Fas antigen-positive YAC-1 cell as a target. We found that DDVP significantly decreased NK, CTL and LAK activities in a dose-dependent manner, and that the CTL and LAK activities of PKO mice were significantly blocked by anti-FasL antibody, suggesting that DDVP and anti-FasL antibody have the same/similar mechanism of inhibiting LAK and CTL activities. We further found that DDVP decreases the expression of Fas antigen on YAC-1 cells, and the expression of FasL on LAK cells in a dose-dependent manner, respectively. Taken together, these findings indicate that the DDVP-induced inhibition of NK, LAK and CTL activities in PKO mice is mediated by the impairment of the FasL/Fas pathway. We also found that DDVP not only significantly inhibited activities of granzymes, but also decreased the intracellular level of perforin, granzyme A and granulysin, which was mediated by inducing degranulation of NK cells and by inhibiting the transcript of mRNA of perforin, granzyme A and granulysin. Taken together, these findings indicate that organophosphorus pesticides inhibited NK, LAK and CTL activities mediated at least by impairment of both the granule exocytosis and FasL/Fas pathways. We are grateful to Professor Krensky AM at Medical School of Stanford University for his helpful advice.
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