| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
(1) Impaired regulatory T cell functions in patients with autoimmune hepatitis
The importance of CD4^+CD25^+regulatory T cell (Tr)-mediated control of self-reactive T cells has been focused on. Recently, several molecules including Foxp3, CTLA4, and GITR (TNFRSF18) were identified as key molecules which control the development and activation of T-reg. We investigated whether there were any difference in the expression pattern of these key molecules on T-reg, and whether there were any difference in the function of T-reg in the patients with type 1 autoimmune hepatitis (AIH). The proportion of T-reg was increased in AIH compared with controls. mRNA for Foxp3 and Ctla4, both molecules are known to activate the function of T-reg, were significantly decreased in AIH compared with controls. We tested if the function of T-reg in AIR was impaired or not after stimulation by OKT3. Although no obvious difference in induction of TNF-α, IFN-γ, and TGF-β was identified, production of IL-10 was sign
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ificantly lower in AIH than in controls. Our results implies the possibility that genetical difference in the expression of Foxp3 and/or CTLA4 on T-reg might lead to the impaired function of T-reg, and finally to the breakthrough of peripheral tolerance in AIH.
(2) Expression of toll-like receptor (TLR) family on regulatory T cells in patients with autoimmune hepatitis
It has been shown that naturally arising T-reg selectively express several members of the TLR family, and that signals through TLRs modulate the function of T-regs. We investigated the expression pattern of TLRs on T-reg in the patients with AIH. Total RNA was extracted from isolated T-reg and non-T-reg fractions and the amount of mRNA for TLR2, 3, 4, 6, 7, 8, 9 were evaluated by real time PCR. In AIH, as well as controls, TLR3, 4, 6, 7, 9 were expressed on Tr. Our results implies the possibility that the signals through TLRs expressed on T-reg might regulate the function of T-reg in AIH. Next we investigated the expression pattern of TLRs on dendritic cells (DCs) in the same manner. Myeloid derived DCs (MDDC) in the peripheral blood of patients with AIH expressed only TLR 6 whereas those of healthy controls expressed TLR 3, 4, 6, 7, 9. Thus Tr might regulated by the signal through the molecules like Foxp3, CTLA-4, and TLR. Further, different expression pattern of TLR on MDDC in AIH might have some influence on functional regulation of Tr by DCs. Less
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