IN VIVO ROLE OF CTLA-4 IN COSTIMULATION AND AUTOIMMUNITY

CTLA-4 在协调刺激和自身免疫中的体内作用

• 批准号: 6349828
• 负责人: Arlene H. Sharpe
• 金额: $ 24.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349828
• 关键词: B lymphocyte; CD28 molecule; T cell receptor; apoptosis; autoimmune disorder; experimental allergic encephalomyelitis; genetically modified animals; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; lymphokines; myelin basic proteins; protein biosynthesis; tissue /cell culture

DESCRIPTION: (Adapted from the Investigator's abstract): The investigator will test the hypothesis that CTLA-4 downregulates T-cell activation and is normally involved in the prevention of autoimmunity. Evidence for this premise comes from the investigator's finding that the CTLA-4-deficient mice develop splenomegaly and lymphadenopathy, multi-organ lymphocytic infiltration and tissue destruction with severe myocarditis and pancreatitis, and die by 3-4 weeks of age. Three specific aims will be tested. The role of CTLA-4 in regulation of T-cell dependent immune responses will be analyzed by determining how CTLA-4 deficiency affects T-cell responses in vitro and whether CTLA-4 mediates its inhibitory effects solely through interactions with B7-1 and B7-2. The mechanisms of CTLA-4-mediated inhibition will be studied using naive and activated T-cells from CTLA-4-deficient, TCR transgenic mice. Emphasis will be placed on susceptibility to apoptosis and lymphokine production. The contribution of CTLA-4 to systemic autoimmune responses will be addressed by assessment of the pathology of in CTLA-4-deficient mice, determination of whether self-reactive T-cells appear in CTLA-4-deficient mice, and whether the course of EAE in MBP-specific TCR transgenic mice is altered when these mice lack CTLA-4.

描述：(改编自《调查员摘要》)：调查员 将检验CTLA-4下调T细胞活化和 通常参与预防自身免疫性疾病。这方面的证据 研究人员发现CTLA-4基因缺陷的小鼠 发展为脾肿大和淋巴结病，多器官淋巴细胞 重症心肌炎合并组织浸润和组织破坏 胰腺炎，并在3-4周大时死亡。三个具体目标将是 测试过。CTLA-4在T细胞依赖性免疫调节中的作用 将通过确定CTLA-4缺乏如何影响反应来分析反应 T细胞体外反应及CTLA-4是否介导其抑制作用 仅通过与B7-1和B7-2的相互作用。它的作用机制 CTLA-4介导的抑制将使用初始和激活的T细胞进行研究 来自CTLA-4缺陷的TCR转基因小鼠。重点将放在 对细胞凋亡和淋巴因子产生的敏感性。的贡献 CTLA-4对全身自身免疫反应的影响将通过评估 CTLA-4基因缺陷小鼠的病理改变 CTLA-4缺陷小鼠体内出现自身反应性T细胞 MBP特异性TCR转基因小鼠的EAE病程发生改变 缺乏CTLA-4。