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 在活化的T细胞上瞬时表达的蛋白，下调T细胞 激活并促进实验动物的耐受性。然而，无论是 这些作用的分子基础，也不是CTLA-4影响细胞增殖的程度。 人类免疫系统是已知。我们的初步发现表明CTLA-4 触发阻断细胞周期进程并促进人CD 4 + T细胞无反应性 细胞，在体外。这个项目的目标是确定分子基础 并确定CTLA-4是否在调节人类T细胞中起作用。 体内的细胞反应。提出了四个具体目标：1）确定 CTLA-4在诱导和维持成人T细胞无反应性中的作用 2）通过引入CTLA-4信号传导来定义CTLA-4信号传导的分子基础 将CTLA-4的选定突变形式和多种信号传导导入人T细胞， 3）确定CTLA-4在调节免疫应答中的作用。 免疫活性SCID/Hu中对自身和非自身抗原的体内应答 小鼠;和4）确定施用抗CTLA-4抗体是否可以逆转 在体内，在模拟肿瘤相关抗原的条件下， 那些在人类癌症中。这些研究的结果不仅可以让我们 确定CTLA-4是否以及如何影响免疫耐受的诱导和维持。 但可能为有效的免疫系统提供基础 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.