IMMUNOPATHOGENESIS OF AIRWAY INFLAMMATION

气道炎症的免疫发病机制

基本信息

批准号：
6640714
负责人：
KIM BOTTOMLY
金额：
$ 41.97万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-12-10 至 2005-02-28
项目状态：
已结题

项目摘要

The overall goal of this proposal is to understand how CD4 T lymphocytes and their associated cytokines regulate the chronic inflammatory disorder which is characteristic of asthma. Asthma airway inflammation involves eosinophils, lymphocytes and mast cells, all of which release chemical mediators in the local lung environment which are thought to cause the observed airway responses. There is considerable evidence that Th2 CD4 effector cells are associated with chronic airway inflammation. In this application, the direct role of Th2 cells and their associated cytokines in the induction of lung inflammatory responses to airway hyperresponsiveness will be tested. Underlying the proposal are 2 hypotheses: First, IL-4, or int he absence of IL-4, IL-13 production by Th2 cells, and subsequent Stat6 signaling by lung endothelial cells are required for Th2 recruitment to the lung. Eosinophil recruitment depends on the presence of Th2 cells and the production of the Th2 cell associated cytokines, IL-4 and IL-5. Second, the appearance of eosinophils in the airway is IL-4 dependent in that in the absence of IL-4, eosinophils in the lung parenchyma do not migrate into the airway. The association of airway eosinophilia with airway responsiveness will be tested. These hypothesis will be tested in 3 Specific Aims: 1) To determine the role of IL-13 and Th2 cell recruitment to the lung; 2) to determine the mechanism by which Th2 derived IL-4 regulates lung and airway eosinophilia; and 3) to determine the cellular molecular and genetic factors that regulate airway eosinophilia following epicutaneous immunization. Using a newly established mouse model in which the Th2 cells and local lung environment can be independently genetically manipulated, the precise function of factors important in the induction of inflammation will be determined.

该提案的总体目标是了解 CD4 T 淋巴细胞如何及其相关细胞因子调节慢性炎症是哮喘的特征性病症。哮喘气道炎症涉及嗜酸性粒细胞、淋巴细胞和肥大细胞，所有这些细胞都释放局部肺部环境中的化学介质被认为引起观察到的气道反应。有大量证据表明 Th2 CD4 效应细胞与慢性气道炎症有关。在此应用中，Th2细胞及其相关细胞的直接作用细胞因子诱导肺部气道炎症反应将测试高反应性。该提案的基础是 2 假设：首先，IL-4，或在缺乏 IL-4、IL-13 的情况下产生 Th2 细胞以及肺内皮细胞随后发出的 Stat6 信号传导 Th2 募集到肺部所需的。嗜酸性粒细胞募集取决于 Th2 细胞的存在和 Th2 细胞的产生相关细胞因子，IL-4 和 IL-5。二、外观气道中的嗜酸性粒细胞是 IL-4 依赖性的，因为在缺乏 IL-4、肺实质中的嗜酸性粒细胞不会迁移到气道中。气道嗜酸性粒细胞增多与气道反应性的关联被测试。这些假设将在 3 个具体目标中得到检验：1) 确定 IL-13 和 Th2 细胞募集至肺部的作用； 2）到确定 Th2 衍生的 IL-4 调节肺的机制气道嗜酸性粒细胞增多； 3) 确定细胞分子和调节表皮后气道嗜酸性粒细胞增多的遗传因素免疫接种。使用新建立的小鼠模型，其中 Th2 细胞和局部肺环境可以独立遗传操纵，诱导中重要因素的精确功能即可确定炎症情况。