In vivo role of CTLA-4 in Costimulation and Autoimmunity

CTLA-4 在共刺激和自身免疫中的体内作用

• 批准号: 6438996
• 负责人: Arlene H. Sharpe
• 金额: $ 29.95万
• 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 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438996
• 关键词: CD28 molecule; T cell receptor; apoptosis; autoimmune disorder; biological signal transduction; cell cell interaction; cell differentiation; cell proliferation; cytokine; genetically modified animals; glomerulonephritis; helper T lymphocyte; humoral immunity; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; ligands; tissue /cell culture

DESCRIPTION (provided by applicant): The B7:CD28/CTLA-4 costimulatory pathway has a critical role in regulating T cell activation, differentiation and tolerance, and is a promising therapeutic target. PD-1 is structurally related to CTLA-4 and has an ITIM motif in its cytoplasmic tail. PD-1 deficient mice develop an autoimmune-like disease. Our recent studies show that the newly discovered B7 homologues, PD-L1 and PD-L2, are ligands for PD-1, and can inhibit T cell proliferation and cytokine production in vitro. The expression of PD-L1 and PD-L2 on nonlymphoid tissues, as well as professional APCs, supports a role for this pathway in regulating peripheral T cell tolerance. The delineation of this pathway has revealed a new means by which T cell responses are regulated, and raised questions about its role in regulating T cell activation and tolerance, and its relationship with the B7:CD28/CTLA-4 pathway. The goals of this project are to investigate the roles of PD-L1 and PD-L2 in regulating T cell activation and tolerance, and interactions between the B7:CD28/CTLA-4 and PD-l:PD-L1/PD-L2 pathways: We will 1) analyze the function of PD-Li and PD-L2 in regulating naive and activated antigen-specific T cells and helper T cell dependent humoral immune responses. We have generated anti-PD-Ll and anti-PD-L2 mAbs and are generating mice lacking PD-L1 and/or PD-L2. These tools provide a definitive means for determining when and how PD-L1 and PD-L2 exert their effects during an immune response, 2) investigate the roles of PD-L1 and PD-L2 in regulating peripheral T cell tolerance. We will use DO.11 TCR Tg T cells to visualize the impact of blockade or elimination of PD-L1 and/or PD-L2 on the responses of antigen-specific CD4+ T cells to immunogenic and tolerogenic stimuli. 3) Analyze the interactions between the PD-1:PD-L1/PD-L2 and B7:CD28/CTLA-4 pathways. We will examine whether these pathways regulate the expression of each other, and evaluate functional interactions. The availability of mice lacking B7-1 and/or B7-2, together with mice lacking CD28 and/or CTLA-4, provide us with unique opportunities to analyze these interactions. These approaches should provide fundamental information about the role of the PD-1:PDL1/PD-L2 pathway in regulating T cell activation and tolerance, and its interactions with the B7:CD28/CTLA-4 pathway. These studies may thereby assist in the design of optimal therapeutic strategies for manipulating the B7:CD28/CTLA-4 pathway and indicate the therapeutic potential of PD-1:PD-L1/PD-L2 pathway manipulation.

描述(申请人提供)：B7：CD28/CTLA-4共刺激通路 在调节T细胞的激活、分化和调节中起关键作用 耐受性，是一个很有前途的治疗靶点。PD-1在结构上是相关的 与CTLA-4结合，其胞质尾部含有ITIM基序。PD-1缺陷小鼠 患上一种自身免疫性疾病。我们最近的研究表明，新的 已发现的B7同系物PD-L1和PD-L2是PD-1的配体，并且可以 体外抑制T细胞增殖和细胞因子的产生。表达方式 PD-L1和PD-L2在非淋巴组织以及专业APC上的表达， 支持该途径在调节外周T细胞耐受性中的作用。这个 对这一途径的描述揭示了T细胞反应的一种新方法 是受调控的，并对其在调节T细胞中的作用提出了质疑 活化和耐受及其与B7：CD28/CTLA-4通路的关系。 本项目的目标是研究PD-L1和PD-L2在 调节T细胞的激活和耐受，以及两者之间的相互作用 B7：CD28/CTLA-4和PD-L：PD-L1/PD-L2通路：我们将1)分析其功能 PD-L1和PD-L2在调节初始和活化抗原特异性T细胞中的作用 辅助性T细胞依赖的体液免疫反应。我们已经产生了 抗PD-L1和抗PD-L2单抗，并产生缺乏PD-L1和/或的小鼠 PD-L2。这些工具为确定时间和方式提供了明确的方法 PD-L1和PD-L2在免疫反应中发挥作用，2)调查 PD-L1和PD-L2在调节外周T细胞耐受中的作用我们会 使用DO.11 TCR TG T细胞来可视化封锁或消除 PD-L1和/或PD-L2对抗原特异性CD4+T细胞免疫应答的影响 免疫原性和耐受性刺激。3)分析企业与企业之间的互动 PD-1：PD-L1/PD-L2和B7：CD28/CTLA-4通路。我们将研究这些是否 这些通路相互调节表达，并评估功能 互动。缺乏B7-1和/或B7-2的小鼠的可用性以及 缺乏CD28和/或CTLA-4的小鼠为我们提供了独特的机会 分析这些交互作用。这些方法应该提供基本的 关于PD-1：PDL1/PD-L2通路在调节T细胞中作用的信息 激活和耐受及其与B7：CD28/CTLA-4通路的相互作用。 因此，这些研究可能有助于设计最佳的治疗方法 操纵B7：CD28/CTLA-4通路的策略和提示 PD-1的治疗潜力：PD-L1/PD-L2通路的操作。