ROLE OF CTLA 4 IN IMMUNE TOLERANCE IN HUMANS

CTLA 4 在人类免疫耐受中的作用

• 批准号: 6514449
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 26.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514449
• 关键词: CD28 molecule; CD3 molecule; SCID mouse; T lymphocyte; acid phosphatase; cyclins; immune tolerance /unresponsiveness; interleukin 2; membrane proteins; mitogen activated protein kinase; mixed tissue /cell culture; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neutralizing antibody; nonhuman therapy evaluation; proliferating cell nuclear antigen; prostate neoplasms; surface antigens; tumor antigens

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.

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质，下调 T 细胞 激活并促进实验动物的耐受性。然而，无论是 这些影响的分子基础以及 CTLA-4 影响的程度 人类的免疫系统是已知的。我们的初步研究结果表明 CTLA-4 触发阻断细胞周期进程并促进人类 CD4+ T 的无反应性 细胞，体外。该项目的目标是定义分子基础 了解这些影响并确定 CTLA-4 是否在调节人类 T 细胞中发挥作用 体内细胞反应。提出了四个具体目标：1）确定 CTLA-4在成人T细胞无反应性诱导和维持中的作用 细胞； 2) 通过引入定义 CTLA-4 信号传导的分子基础 进入人类 T 细胞中选定的 CTLA-4 突变形式和各种信号传导 中间体； 3)确定CTLA-4在免疫调节中的作用 免疫活性 SCID/Hu 体内对自身和非自身抗原的反应 老鼠； 4) 确定给予抗 CTLA-4 抗体是否可以逆转 在体内模拟条件下对肿瘤相关抗原的耐受性 那些在人类癌症中。这些研究的结果不仅应该让我们 确定 CTLA-4 是否以及如何影响耐受诱导和维持 人类，但有可能为有效的免疫治疗提供基础 癌症的方法。