MECHANISMS OF TOLERANCE--APOPTOSIS

耐受机制——细胞凋亡

• 批准号: 2649922
• 负责人: David Linn Perkins
• 金额: $ 19.19万
• 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: 1997-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2649922
• 关键词: T cell receptor; T lymphocyte; apoptosis; autoimmune disorder; biological signal transduction; genetically modified animals; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; tissue /cell culture

The long term goal of our laboratory is to understand the mechanisms of peripheral T cell tolerance. In previous work we have analyzed three phases of tolerance induction characterized by T cell activation, apoptosis, and anergy in both normal mice and spontaneously autoimmune 1pr strain. In general, these results indicate that tolerance induction in vivo involves multiple mechanisms. The focus of Aims 1 and 2 of this proposal is to analyze the mechanisms regulating apoptosis and maintaining anergy. We have adapted techniques to identify and isolate activated and apoptotic T cells in T cell receptor transgenic mice during tolerance induction that permit both phenotypic and functional analysis. These results should provide important insight into the mechanisms of T cell tolerance induction. Defective tolerance promotes autoimmune disease. In Aim 3 we will investigate the role of defective apoptosis in the pathogenesis of autoimmunity. Our preliminary results indicate that expression of the T cell receptor beta chain transgene inhibits T cell activation with aging and thus prevents autoimmunity. Based on these results, we propose an exciting model of 1pr autoimmunity using T cell receptor alpha beta transgenic mice which can be experimentally manipulated by exogenous antigen. This permits initiating and stopping the autoimmune process at pre determined time points. Our model should provide a powerful tool to investigate both apoptosis and the accumulation of atypical double negative T cells in the pathogenesis of autoimmunity.

我们实验室的长期目标是了解 外周T细胞耐受性在以前的工作中，我们分析了三个 以T细胞活化为特征的耐受诱导阶段， 正常小鼠和自发性自身免疫性1pr 株一般而言，这些结果表明， 体内涉及多种机制。本报告的目标1和2的重点是 我们的建议是分析细胞凋亡的调控机制， 无反应我们已经采用了技术来识别和分离激活的， T细胞受体转基因小鼠耐受过程中T细胞凋亡的研究 允许表型和功能分析诱导。这些 这些结果将为深入了解T细胞免疫的机制提供重要的信息。 耐受诱导免疫耐受缺陷会导致自身免疫性疾病。在 目的3：探讨凋亡缺陷在细胞凋亡中的作用。 自身免疫的发病机制。我们的初步结果表明， T细胞受体β链转基因的表达抑制T细胞 激活与老化，从而防止自身免疫。基于这些 结果，我们提出了一个令人兴奋的1pr自身免疫模型，使用T细胞 受体α β转基因小鼠， 由外源抗原操纵。这允许启动和停止 在预定的时间点进行自身免疫过程。我们的模型应该提供 这是一个研究细胞凋亡和细胞内毒素积累的有力工具， 非典型双阴性T细胞在自身免疫发病机制中的作用