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）：本项目的长期目标是 定义调节细胞的分子、细胞和遗传机制， 哮喘和过敏性疾病的发展。在之前的申请中 在此期间，我们研究了促进和加强Th 2偏向免疫的过程 应答我们现在建议检查免疫机制，防止 Th 2反应的发展，以及逆转建立的Th 2偏向反应 哮喘和过敏性疾病。具体来说，我们将研究保护性 抗原特异性T细胞对过敏性疾病和哮喘的作用 呼吸道暴露于抗原后诱导的耐受和保护 用佐剂热灭活单核细胞增生李斯特菌免疫诱导 (HKL)是先天免疫系统的强力刺激物我们有令人兴奋 初步数据表明，呼吸道暴露于过敏原诱导 T细胞耐受性，阻止Th 2反应和气道的发展 高反应性，并且由肺树突状细胞主动介导 能瞬时产生IL-10我们将研究肺树突状细胞的作用， 细胞和定义的细胞和分子事件，呼吸道抗原 诱导T细胞耐受性。此外，我们还将研究 HKL作为佐剂诱导的T细胞对免疫调节的耐受性，和 研究TGF-β、IL-10、CD 8细胞和Toll样受体的作用 HKL下调已建立的Th 2偏向性应答过程中的信号传导 最后，使用一种独特的同类BALB/c小鼠品系， 气道高反应性的发展，并产生低水平的IL-4，我们将 描述了一个特定的遗传元件，Tapr，我们已经确定了 11号染色体，并下调气道的发展 CD 4 + T细胞的高反应性和IL-4产生。 这些研究将描绘细胞和分子基础， 哮喘和变态反应中Th 2应答的免疫调节， 哮喘和过敏性疾病的新治疗方法。此类疗法 不仅能消除Th 2炎症，还能替代过敏性 具有“保护性”免疫力的炎症可能会提供长期的 治疗哮喘和过敏性疾病。