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分子、细胞和遗传机制 哮喘和过敏性疾病的发展。上次申请期间 在此期间，我们研究了促进和强化 Th2 偏向免疫的过程 回应。我们现在建议检查免疫机制，以防止 Th2 反应的发展，并逆转已建立的 Th2 偏向反应 哮喘和过敏性疾病。具体来说，我们将检查保护措施 抗原特异性 T 细胞对过敏性疾病和哮喘的作用 呼吸道接触抗原后诱导的耐受性和保护 通过佐剂热灭活单核细胞增生李斯特菌免疫诱导 (HKL) 是先天免疫系统的有效刺激剂。我们有令人兴奋的 初步数据表明，呼吸道接触过敏原会诱发 T 细胞耐受性，可阻止 Th2 反应和气道的发展 高反应性，由肺树突状细胞主动介导 瞬时产生 IL-10。我们将研究肺树突的作用 细胞并定义呼吸道抗原的细胞和分子事件 诱导 T 细胞耐受。此外，我们将检查以下关系： T细胞对HKL作为佐剂诱导的免疫调节的耐受性，以及 研究 TGF-β、IL-10、CD8 细胞和 Toll 样受体的作用 HKL 下调已建立的 Th2 偏向反应期间的信号传导 最后，使用独特的同类 BALB/c 小鼠品系来抵抗 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件 Tapr 11 号染色体下调气道发育 CD4+ T 细胞的高反应性和 IL-4 的产生。 这些研究将描述细胞和分子基础 哮喘和过敏中 Th2 反应的免疫调节，并应导致 哮喘和过敏性疾病的新治疗方法。此类疗法 不仅能消除Th2炎症，还能替代过敏 具有“保护性”免疫力的炎症可能会提供长期的保护 治疗哮喘和过敏性疾病。