ROLE OF T LYMPHOCYTES IN AIRWAY HYPERRESPONSIVENESS

呼吸道炎症目前被认为是主要的致病因素 导致呼吸道高反应性的机制。虽然很多人 不同的细胞类型及其产物有助于 致敏患者的呼吸道炎症反应或 对于动物来说，T淋巴细胞似乎起着关键作用。T 淋巴细胞调节IgE的产生并分泌大量的 促炎症细胞因子，其中之一，IL-5，控制嗜酸性粒细胞 生产、激活和生存。这样做的目的是 建议是描述体液和细胞中介的作用 免疫在呼吸道高反应性发展中的作用vbl.使用 通过呼吸道的过敏原致敏的小鼠模型，我们有 确定了以下三个基本组件的融合 气道反应性改变的发展，通过抗原攻击 呼吸道，产生(一致的)抗原特异性IgE， T细胞的抗原依赖性激活(包括CD4+和 CD8+)导致IL-5产生和嗜酸性粒细胞聚集 肺部。利用免疫学和遗传操作，我们现在将 明确抗原特异性免疫球蛋白E在扩增 T细胞的招募、扩增和分化，可能是通过 与B细胞表面CD23结合。我们将描述这个角色的特点 单个T细胞亚群在改变的发展中发挥作用 在裸鼠体内过继转移T细胞引起的呼吸道反应， 分析这些细胞的细胞因子谱和归巢反应 在呼吸道挑战之后。利用IL-5和IL-4缺乏 小鼠，我们将确定这些细胞因子在 嗜酸性炎症的发展。基于先前的研究 雾化吸入干扰素-γ调节这些细胞因子的有效性 抗原特异性反应，我们将定义这一点如何重要 调节性细胞因子改变B和T细胞功能以使其正常化 主要或继发性变应原引起的呼吸道反应性 挑战。这些研究将确定重要的免疫学 对获得改变的呼吸道反应性的贡献， 为更好地了解该病的发病机制铺平了道路 哮喘和新的治疗选择的发展。

Airway inflammation is currently regarded as the major pathogenetic mechanism leading to airway hyperresponsiveness. Although many different cell types and their products contribute to the inflammatory reaction in the airways of sensitized patients or animals, the T lymphocyte appears to play a pivotal role. T lymphocytes regulate IgE production and secrete a number of proinflammatory cytokines, one of which, IL-5, controls eosinophil production, activation and survival. The objectives of this proposal are to delineate the roles of humoral and cell-mediated immunity in the development of airway hyperresponsiveness. Using a murine model of allergen-sensitization via the airways, we have identified the convergence of three essential components in the development of altered airway responsiveness, antigen challenge via the airways, the production of (concordant) antigen-specific IgE, and the antigen-dependent activation of T cells (both CD4+ and CD8+) resulting in IL-5 production and eosinophil accumulation in the lung. Using immunologic and genetic manipulations, we will now define the role antigen-specific IgE plays in the amplification of T-cell recruitment, expansion and differentiation, perhaps through binding to CD23 on B cells. We will characterize the role individual T-cell subsets play in the development of the altered airway response using adoptive transfer of T cells in nude mice, analyzing cytokine profiles of these cells and homing responses following airway challenge. Utilizing IL-5 and IL-4 deficient mice, we will identify the role of these cytokines in the development of eosinophilic inflammation. Based on prior studies of the efficacy of nebulized interferon-gamma to modulate these antigen-specific responses, we will define how this important regulatory cytokine alters B and T-cell function to normalize airway responsiveness following primary or secondary allergen challenge. These studies will identify the important immunologic contributions to the acquisition altered airway responsiveness, paving the way to a better understanding of the pathogenesis of asthma and the development of novel therapeutic options.