Differential Activation Requirements of CD4+ T Cells

CD4 T 细胞的差异激活要求

• 批准号: 6382727
• 负责人: Rosemarie H DeKruyff
• 金额: $ 35.89万
• 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: 2001-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382727
• 关键词: B lymphocyte; Listeria; bacterial antigens; cellular immunity; cytokine receptors; cytotoxic T lymphocyte; dendritic cells; genetic mapping; helper T lymphocyte; immune tolerance /unresponsiveness; interleukin 10; interleukin 4; laboratory mouse; leukocyte activation /transformation; microarray technology; ovalbumin; protein biosynthesis; respiratory hypersensitivity; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): The long-term goals of this project are to define the molecular, cellular and genetic mechanisms that regulate the development of asthma and allergic diseases. During the previous application period we studied processes that promote and intensify Th2 biased immune responses. We now propose to examine immune mechanisms that prevent the development of Th2 responses, and that reverse established Th2-biased responses in asthma and allergic diseases. Specifically, we will examine the protective effects against allergic disease and asthma afforded by antigen-specific T-cell tolerance induced following respiratory exposure to antigen, and protection induced by immunization with the adjuvant heat killed Listeria monocytogenes (HKL) a potent stimulator of the innate immune system. We have exciting preliminary data demonstrating that respiratory exposure to allergen induces T-cell tolerance, which prevents the development of Th2 responses and airway hyperreactivity, and which is actively mediated by pulmonary dendritic cells that transiently produce IL-10. We will study the role of pulmonary dendritic cells and define the cellular and molecular events by which respiratory antigen induces T-cell tolerance. In addition, we will examine the relationship of T-cell tolerance to immune modulation induced by HKL as adjuvant, and investigate the role of TGF-beta, IL-10, CD8 cells, and Toll-like receptor signaling during the down-regulation of established Th2 biased responses by HKL Finally, using a unique congenic BALB/c mouse strain that resists the development of airway hyperreactivity and produces low levels of IL-4, we will characterize a specific genetic element, Tapr, that we have identified on chromosome 11 and which down-modulates the development of airway hyperreactivity and IL-4 production in CD4+ T-cells. These studies will delineate the cellular and molecular basis for immunoregulation of Th2 responses in asthma and allergy, and should lead to novel therapeutic approaches for asthma and allergic disease. Such therapies will not only eliminate Th2 inflammation, but also replace allergic inflammation with "protective" immunity that potentially will provide long-term cure for asthma and allergic diseases.

描述（由申请人提供）：该项目的长期目标是定义调节调节的分子，细胞和遗传机制 哮喘和过敏性疾病的发展。在上一个申请中 我们研究了促进和加强Th2偏置免疫的过程 回答。我们现在建议检查防止的免疫机制 TH2响应的发展，并反向建立的Th2偏向响应 在哮喘和过敏性疾病中。具体来说，我们将检查保护性 针对抗原特异性T细胞提供的过敏性疾病和哮喘的影响 呼吸道暴露于抗原和保护后引起的耐受性 通过辅助热诱导的免疫诱导李斯特菌单核细胞增生李斯特菌 （HKL）先天免疫系统的有效刺激剂。我们很激动 初步数据表明，呼吸道暴露于过敏原诱导 T细胞耐受性，可防止TH2响应和气道的发展 过度反应性，并由肺树突细胞积极介导 该瞬时产生IL-10。我们将研究肺树突的作用 细胞并定义呼吸抗原的细胞和分子事件 诱导T细胞耐受性。此外，我们将研究 HKL作为佐剂诱导的T细胞耐受性对免疫调节的耐受性， 研究TGF-β，IL-10，CD8细胞和Toll样受体的作用 HKL下调建立的Th2偏置响应的信号传导 最后，使用独特的先天性BALB/C小鼠应变 气道高反应性的发展并产生低水平的IL-4，我们将 表征我们已经确定的特定遗传元素TAPR 11号染色体，并减少气道的发展 CD4+ T细胞中的高反应性和IL-4产生。 这些研究将描绘出细胞和分子基础 哮喘和过敏中Th2反应的免疫调节，应导致 哮喘和过敏性疾病的新型治疗方法。这种疗法 不仅会消除TH2炎症，还可以替换过敏 具有“保护性”免疫力的炎症可能会提供长期 治愈哮喘和过敏性疾病。