ROLE OF CTLA 4 IN IMMUNE TOLERANCE IN HUMANS

描述：(改编自申请人的摘要)CTLA-4，一种跨膜 蛋白在激活的T细胞上瞬时表达，下调T细胞 激活并促进实验动物的耐受性。然而，无论是 这些效应的分子基础，也不知道CTLA-4对 人类的免疫系统是已知的。我们的初步调查结果表明，CTLA-4 触发阻断细胞周期进程并促进人CD4T细胞无能 细胞，在体外。这个项目的目标是定义分子基础 并确定CTLA-4是否在调节人类T细胞中起作用 活体内的细胞反应。提出了四个具体目标：1)确定 CTLA-4在成人T细胞无能诱导和维持中的作用 细胞；2)定义CTLA-4信号的分子基础 进入人类T细胞的CTLA-4的选择突变形式和各种信号 中间体；3)确定CTLA-4在免疫调节中的作用 免疫活性SCID/Hu在体内对自身和非自身抗原的反应 以及4)确定给予抗CTLA-4抗体是否能逆转 体内对肿瘤相关抗原的耐受性，在模拟条件下 那些患有人类癌症的人。这些研究的结果不仅应该让我们能够 确定CTLA-4是否以及如何影响耐受性诱导和维持 但有可能为有效的免疫治疗提供基础 接近癌症。

DESCRIPTION: (Adapted from applicant's abstract) CTLA-4, a transmembrane protein expressed transiently on activated T cells, downregulates T cell activation and promotes tolerance in experimental animals. However, neither the molecular basis for these effects nor the extent to which CTLA-4 influences the human immune system are known. Our preliminary findings indicate that CTLA-4 triggering blocks cell cycle progression and promotes anergy in human CD4+ T cells, in vitro. The goals of this project are to define the molecular basis for these effects and determine if CTLA-4 plays a role in regulating human T cell responses, in vivo. Four specific aims are proposed: 1) to determine the function of CTLA-4 in the induction and maintenance of anergy in adult human T cells; 2) to define the molecular basis for CTLA-4 signalling by introducing into human T cells selected mutant forms of CTLA-4 and a variety of signalling intermediates; 3) to determine the role of CTLA-4 in regulating the immune response to self and non-self antigens, in vivo, in immunocompetent SCID/Hu mice; and 4) to determine if administration of anti-CTLA-4 antibody can reverse tolerance to a tumor associated antigen, in vivo, under conditions that mimic those in human cancer. The results of these studies should not only allow us to determine if and how CTLA-4 affects tolerance induction and maintenance in humans but potentially provide the basis for an effective immunotherapeutic approach to cancer.