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Analysis of the molecular machaism of defective T cell functions in reqularing B cell activation in various autoimmune diseases

多种自身免疫性疾病中T细胞功能缺陷调节B细胞活化的分子机制分析

基本信息

批准号：
10670428
负责人：
HIROHATA Shunsei
金额：
$ 2.05万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670428/
关键词：
IL-12 IFN-γ TH1 Th2 cyclin A mizoribine Fas CD40L anti-CD3 CD4+T細胞免疫グロブリン免疫抑制薬ミゾリビン SLE Fas アポトーシス

项目摘要

Although human T cells have been shown to regulate humoral immune responses by directly inhibiting B cells, the precise sequelae for the mechanism of suppression have not yet been delineated. The present study therefore examined the nature of T cell-B cell collaboration to suppress B cell responses. Special attention was directed to the role of Fas (CD95)-Fas ligand (FasL) interactions and CD40-CD40 ligand (CD40L) interactions. The results indicate that signals achieved by direct interactions through CD40-CD40L exert bidirectional effects on the outcome of humoral immune responses depending on the state of activation of B cells and on the extent of CD40 ligation. Moreover, the data suggest that CD40-CD40L interactions rather than Fas-FasL interactions may play more critical roles in direct cellular collaboration between B cells and anti-CD3 stimulated CD4+ T cells to prevent the extention of responses of inappmpriately activated B cells.IL-12 is the prominent inducer of Th1 responses i … More n human and in the mouse. CD40L plays important roles in regulation of immune responses, including T cell-dependent activation of B cells and cytokine production by monocytes and dendritic cells. We next examined the influences of IL-12 on the CD40L expression a activated human CD4+ T cells. The results indicate that IL- 12 enhances the CD40L expression of activated CD4+ T cells independently of the IFN-γ production. The data thus suggest that Th1 responses induced by IL-12 might play an important role in regulation of humoral immune responses through up-regulated CD40L expression.Mizoribine has been shown to have beneficial effects in the treatment of rheumatoid arthritis and lupus nephritis, in which abnormal B cell functions are involved. Previous studies demonstrated that mizoribine directly suppresses the function of human B cells. We explored in detail the mechanism of the suppression of human B cell responses by mizoribine at the molecular level. The results indicate that mizoribine suppresses the expression of cyclin A mRNA in human B cells by downregulating its stability, and thus downregulates their responses. Less

虽然人类T细胞已被证明可以通过直接抑制B细胞来调节体液免疫应答，但抑制机制的精确后遗症尚未被描述。因此，本研究探讨了T细胞-B细胞协作抑制B细胞反应的性质。特别关注Fas（CD 95）-Fas配体（FasL）相互作用和CD 40-CD 40配体（CD 40 L）相互作用的作用。结果表明，通过CD 40-CD 40 L直接相互作用获得的信号对体液免疫应答的结果产生双向影响，这取决于B细胞的活化状态和CD 40连接的程度。CD 40-CD 40 L相互作用可能在B细胞和抗CD 3刺激的CD 4 + T细胞之间的直接细胞协作中发挥更重要的作用，以防止不适当激活的B细胞的反应扩展。 ...更多信息在人类和小鼠中。CD 40 L在免疫应答的调节中起重要作用，包括T细胞依赖性的B细胞活化以及单核细胞和树突状细胞的细胞因子产生。我们接下来检查了IL-12对活化的人CD 4 + T细胞的CD 40 L表达的影响。结果表明，IL- 12增强活化的CD 4 + T细胞的CD 40 L表达，而与IFN-γ的产生无关。提示IL-12诱导的Th 1应答可能通过上调CD 40 L表达在体液免疫应答中起重要调节作用，咪唑立宾在治疗B细胞功能异常的类风湿性关节炎和狼疮性肾炎中具有有益作用。以前的研究表明，咪唑立宾直接抑制人B细胞的功能。我们在分子水平上详细探讨了咪唑立宾抑制人B细胞反应的机制。结果表明，咪唑立宾通过下调细胞周期蛋白A的稳定性来抑制人B细胞中细胞周期蛋白A mRNA的表达，从而下调它们的反应。少