Differential Activation Requirements of CD4+ T Cells

描述(由申请人提供)：本项目的长期目标是确定调节细胞周期的分子、细胞和遗传机制 哮喘和过敏性疾病的发展。在上一次申请期间 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应答的发展，以及逆转已建立的Th2偏向应答 哮喘和过敏性疾病。具体地说，我们将检查保护性 抗原特异性T细胞抗过敏性疾病和哮喘的作用 呼吸道暴露抗原诱导的耐受性及其保护 热杀灭单核细胞增生性李斯特菌佐剂免疫诱导 (HKL)天然免疫系统的有力刺激物。我们有令人兴奋的 初步数据显示，呼吸道暴露于变应原会导致 T细胞耐受性，防止Th2反应和呼吸道的发展 高反应性，并由肺树突状细胞主动介导 会瞬间产生IL-10。我们将研究肺树突状细胞的作用 细胞，并定义呼吸道抗原通过哪些细胞和分子事件 诱导T细胞耐受。此外，我们还将研究 T细胞对HKL作为佐剂诱导的免疫耐受，以及 探讨转化生长因子-β、IL-10、CD8细胞和Toll样受体的作用 HKL下调已建立的Th2偏向应答过程中的信号 最后，使用一种独特的同源BALB/c小鼠品系，该品系可以抵抗 发生呼吸道高反应性并产生低水平的IL-4，我们将 描述一种特定的遗传元素，TAPR，我们已经在 11号染色体，它下调呼吸道的发育 CD4+T细胞的高反应性和IL-4的产生。 这些研究将描绘出细胞和分子基础 哮喘和变态反应中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。这样的疗法 不仅会消除Th2炎症，还会取代过敏症 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。

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.