| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
We have previously found that both IL-12 p40 and p35 mRNA expression is enhanced by the interaction between T cells and antigen-presenting cells (APC) in the presence of antigen. In the present study, we have examined the mechanism to enhance the 35 mRNA expression and revealed that the signalling through MHC class II is important for the p35 mRNA enhancement. Moreover, we have examined on the necessity of priming by IFN-γ for IL-12 production as reported by others, and found that the priming by IFN-γis not essential for IL-12 production and only adhering of macroohages to culture dish is enough for it.
We have examined the effect of signalling through CD28 and CTLA-4 on IL-12 receptor (R) expression and have found that the signalling through CD28 positively regulates both IL-12Rβ1 and β2 mRNA expression and that through CTLA-4 negative regulates it. The similar effect was also observed even using IFN-γ knockout (KO) mice. These results further suggest the importance of interaction betw
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een CD28/CTLA-4-B7-1/2 in the regulation of IL-12R expression. In addition, we have found that the signalling through CTLA-4 augments the differentiation to Th1 cells independent on IL-12 but partially dependent on TGF-β.
We have examined the effector mechanism located downstream IL-12 and IFN-γ, whose production is for the host resistance, in the infection with blood-stage Plasmodium berghei XAT.The experiments using iNOS KO and FcR γ-chain KO mice and those using anti-NK1.1 depleting mAb have revealed that NO production and NK activation, both of which are seen after the infection, are not critical for the host resistance but FcR-mediated Ab-dependent phagocytosis is important for it.
The transgenic Ipr mice, in which p40 is highly and specifically expressed in liver, have shown reduced levels of serum NO and IFN-γ production, anti-DNA Ab titer and proteinuria, although they developed lymphadenopathy as wild-type mice did. The transgentc NOD mice, in which p40 is specifically expressed in islet by regulating with glucagon promoter without affecting serum level of p40, have exhibited significant suppressive effects on the development of diabetes. These results suggest that p40 has a potential therapeutic effect on the development of autoimmune diseases. Less
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