ACTIVATION OF T CELLS MEDIATING AIRWAY HYPERREACTIVITY

哮喘是一种复杂的疾病，被认为是异常的免疫反应。 对通过气道遇到的环境抗原的反应性。 将Th 2型应答与肺病理学联系起来的各种假设， 已被提议用于哮喘，但人类研究仍然与此相关。 时间气道对雾化抗原的反应性的小鼠模型已经被研究。 建立，将允许划定的关键途径， 气道生理和免疫反应得以建立， 调解。 该模型涉及动物对卵清蛋白的致敏， 已经确定了CD 4 + T细胞和白细胞介素（IL）的关键要求- 4在最初暴露于抗原期间。我们建议使用特定的 确定不存在各种免疫缺陷的试剂和敲除动物 分子来探测分化的分子事件， 诱导气道反应性所需的效应T细胞， 介导气道反应性的效应器途径。在一系列的四个 为了达到相互关联的目的，我们将（1）建立IL-4的动力学 在预充过程中的要求，并阐明所需的IL-4的来源， 病理诱导T细胞的发育;（2）描述需求 用于通过CD 28-B7和CD 40-CD 40 L配体系统的共刺激;（3） 测试通过绕过必要的条件来消除病理反应的能力 使用改变的T细胞受体配体的共刺激途径;和（4）使用 MHC II类限制性T细胞受体转基因小鼠在两个不同的 在引发期间产生不同量的IL-4的遗传背景 为了使用野生型来测试在先前目的中产生的假设， 小鼠转基因TCR气道高反应性模型的建立 小鼠在定义系统中将是重要的，在该系统中， 反应性T细胞可以产生用于实验目的， 开始分析遗传易感性对 免疫病理性肺病的发展。

Asthma is a complex disease believed to reflect aberrant immune responsiveness to environmental antigens encountered through the airway. Various hypotheses that link Th2-type responses with lung pathology have been proposed for asthma, but human studies remain correlative at this time. A mouse model of airway reactivity to aerosolized antigens has been established that will permit delineation of the critical pathways by which airway physiologic and immunologic responses become established and are mediated. This model, involving sensitization of animals to ovalbumin, has identified crucial requirements for CD4+ T cells and interleukin (IL)- 4 during the initial exposure to antigen. We propose to use specific reagents and knock-out animals with defined absence of various immune molecules to probe molecular events underlying the differentiation of effector T cells required for the induction of airway reactivity and the effector pathways that mediate airway reactivity. In a series of four interrelated aims, we will (1) establish the kinetics for IL-4 requirements during priming and elucidate the source of IL-4 required for the development of pathology-inducing T cells; (2) delineate requirements for costimulation through the CD28-B7 and CD40-CD40L ligand systems; (3) test the ability to abrogate pathologic responses by bypassing requisite costimulatory pathways using altered T cell receptor ligands; and (4) use MHC class II-restricted T cell receptor transgenic mice on two different genetic backgrounds that produce differing amounts of IL-4 during priming in order to test hypotheses generated in the prior aims using wild-type mice. Establishing models for airway hyperreactivity in transgenic TCR mice will be important in defining systems in which greater numbers of reactive T cells can be generated for experimental purposes and in beginning to analyze the influence of genetic predisposition on the development of immunopathologic lung disease.