ACTIVATION OF T CELLS MEDIATING AIRWAY HYPERREACTIVITY

哮喘是一种复杂的疾病，被认为反映了异常的免疫。 对通过呼吸道遇到的环境抗原的反应。 将Th2型反应与肺部病理联系起来的各种假说 已被提议用于哮喘，但人类研究仍与此相关 时间到了。一种小鼠呼吸道对雾化抗原的反应性模型已经被证实。 将允许描绘关键路径的关键路径的建立 建立了呼吸道生理和免疫反应，并 调解过的。这个模型涉及到动物对卵清蛋白的敏化， 已经确定了对CD4+T细胞和白细胞介素1(IL)的关键需求- 4在初次接触抗原期间。我们建议使用特定的 明显缺乏各种免疫的试剂和基因敲除动物 分子来探测导致细胞分化的分子事件 诱导呼吸道反应性所需的效应器T细胞和 调节呼吸道反应性的效应器通路。在四个系列中 相关目标，我们将(1)建立IL-4的动力学 在启动过程中的要求并阐明所需的IL-4的来源 病理诱导T细胞的发展；(2)描述需求 通过CD28-B7和CD40-CD40L配体系统进行共刺激；(3) 测试通过绕过必需品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通路；以及(4)使用 MHC II类限制性T细胞受体转基因小鼠在两种不同的 在启动过程中产生不同数量IL-4的遗传背景 为了使用野生型来检验在先前目标中产生的假设 老鼠。转基因TCR气道高反应性模型的建立 在定义系统时，鼠标将非常重要，在该系统中， 反应性T细胞可以用于实验目的，并在 开始分析遗传易感性对老年人心理健康的影响 免疫病理肺病的进展。

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.