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Roles of regulatory T cells (Tr) and dendritic cells (DCs) in the pathogenesis of autoimmune hepatitis(AIH)

调节性T细胞（Tr）和树突状细胞（DC）在自身免疫性肝炎（AIH）发病机制中的作用

基本信息

批准号：
16590644
负责人：
OKUMURA Akihiko
金额：
$ 2.3万
依托单位：
Aichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

(1) Impaired regulatory T cell functions in patients with autoimmune hepatitisThe 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 … More 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 hepatitisIt 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

(1)自身免疫性肝炎患者调节性T细胞功能受损研究主要集中在CD4~+CD25~+调节性T细胞(Tr)对自身反应性T细胞的调节作用。最近，包括Foxp3、CTLA4和GITR(TNFRSF18)在内的几个分子被确定为控制T-reg发生和激活的关键分子。我们研究了1型自身免疫性肝炎(AIH)患者T-reg上这些关键分子的表达模式是否存在差异，T-reg的功能是否存在差异。AIH组T-reg比例高于对照组。AIH患者外周血中激活T-reg功能的分子Foxp3和CTLA4的表达水平显著低于对照组。检测OKT3刺激后空气中T-reg功能是否受损。尽管在诱导肿瘤坏死因子-α、干扰素-γ和转化生长因子-β方面没有明显差异，但IL-10的产生是标志…AIH组明显低于对照组。我们的结果提示，T-reg上Foxp3和/或CTLA4表达的遗传差异可能导致T-reg功能受损，最终导致AIH患者外周耐受的突破。(2)自身免疫性肝炎患者调节性T细胞上Toll样受体(Toll-like Receptor，TLR)家族的表达已表明，自然产生的T-reg选择性地表达TLR家族的几个成员，并通过TLRs信号调节T-regs的功能。我们研究了AIH患者T-reg上TLRs的表达模式。从分离的T-reg组分和非T-reg组分中提取总RNA，用实时荧光定量聚合酶链式反应(Real Time PCR)检测TLR2、3、4、6、7、8、9的mRNA含量。AIH组和对照组TLR3、4、6、7、9在Tr上均有表达。我们的结果提示，T-reg上表达的TLRs信号可能在AIH中调节T-reg的功能。接下来，我们以同样的方式研究了树突状细胞(DC)上TLRs的表达模式。AIH患者外周血中髓系树突状细胞(MDDC)仅表达TLR6，而健康人外周血中表达TLR3、4、6、7、9，提示Tr可能通过Foxp3、CTLA-4、TLR等分子受信号调节。此外，AIH患者MDDC上TLR的不同表达模式可能对DC对Tr的功能调节有一定影响。较少