T CELL CYTOKINE/ADHESION MOLECULE REGULATION IN ASTHMA

控制主要免疫球蛋白E的T细胞的鉴定 通过与B细胞的直接相互作用和通过 可溶性细胞因子白介素4(IL-4)的研究进展 最近发现的CD4T辅助细胞在体内的作用 哮喘的发生使T细胞的功能在对 哮喘患者的肛周过敏原或暴露在其中的过敏原是一种严重的 问题。这项提案的具体目标看起来是为了 参与独特细胞因子基因的转录活性因子 在T细胞水平激活，特别是IL-4，并延长这些 具体目的是检查这些差异表达 T细胞克隆系中T细胞调节因子的研究 哮喘患者家庭。我们将尝试将相关描述与 这些新因素与哮喘的易感性在基因水平上有关。 特定目的1识别和表征转录因子 是T细胞IL-4基因激活所必需的。在这些实验中，我们 将评估和表征提取的蛋白质因子的细胞核 过敏原特异性T细胞株和过敏原特异性T细胞克隆 为了影响IL-4基因的转录，我们将检测 这些蛋白质提取物与启动子片段基序结合 被发现在调节IL-4的激活中起重要作用。我们会 纯化并最终测序和克隆与这些疾病有关的基因 转录因子和研究其表达的开发试剂 在各种情况下。在《特定目标2》中，我们将考察 已鉴定的IL-4转录因子的表达 特应性T细胞系和克隆的使用。对实际情况的审查 这些过敏原触发的细胞对IL-4和IL-5使用的选择将 也进行，因为这些因素可以确定特应性疾病的危险因素 还有哮喘。在具体的目标3中，我们将查看 过敏原来源的T细胞中转录因子的表达 在IgE升高和哮喘的亲属家庭中的未受影响的个体。 在这一特定的目标下，提出了实验来详细地检验T 人外周血中转录因子的细胞系表达 紧随其后的是患有过敏症和哮喘的未受影响和受影响的家庭成员 长期在国家犹太人监狱服刑。将对激活进行分析 这些过敏原特异性和变态反应的概况和差异 控制T细胞并试图将这些发现与 一家系哮喘患者的临床治疗措施 就这样吧。最后，在特定的目标4中，我们将检查由过敏原驱动的 哮喘患者呼吸道和外周血T细胞黏附分子的表达 哮喘。这些研究将对评估潜力具有重要意义。 哮喘患者T细胞在呼吸道内蓄积的机制 特定过敏原的影响。这些研究将确定潜在的 T细胞细胞因子通路在慢性阻塞性肺疾病永存中的作用机制 哮喘中的呼吸道炎症。

The identification of T cells as being in control of the major IgE regulatory switch through their interaction directly with B cells and via the elaboration of the soluble cytokine, interleukin-4 (IL-4), and the recent identification of the in vivo role of CD4+T helper cells into generation of asthma make the function of T cells in the response to perianal allergen or exposed allergen in asthmatic airways a critical issue. Specific aims of this proposal look to characterize transcriptionally active factors involved in unique cytokine gene activation, specifically IL-4, at the T cell level and to extend these specific aims to an examination of the differential expression of these T cell regulatory factors at the T cell clone line in kindreds of asthmatic families. An attempt will be made to correlate description of these new factors with susceptibility to asthma at the genetic level. Specific Aim 1 identifies and characterizes transcription factors necessary for IL-4 gene activation in T cells. In these experiments we will assess and characterize protein factors extracted nuclei of allergen-specific T cell lines as well as allergen-specific T cell clones to influence the transcription of IL-4 genes We will examine the ability of these protein extracts to bind promoter fragment motifs that have been found to be important in the regulation of IL-4 activation. We will purify and eventually sequence and clone the genes responsible for these transcription factors and develop reagents to study their expression under various circumstances. In Specific Aim 2 will examine the expression of the previously identified transcription factors for IL-4 usage by atopic T cell lines and clones. An examination into the actual selection of IL-4 and IL-5 usage by these allergen triggered cells will also be conducted since these factors may identify risk factors for atopy and asthma. In Specific Aim 3, we will look at the expression of transcription factors in allergen derived T cells from affected and unaffected individuals in kindred families with elevated IgE and asthma. In this specific aim, experiments are proposed to examine in detail T cell line expression of transcription factors from individuals from unaffected and affected family members with atopy and asthma followed longterm at National Jewish. Analysis will be made of the activation profiles and differences in the response of these allergen specific and control T cell and an attempt to correlate these findings with the clinical measures of asthma in a large kindred of asthmatic families will be done. Finally, in Specific Aim 4 we will examine the allergen-driven expression of airway and peripheral blood T cell adhesion molecules in asthma. These studies will be important to evaluate the potential mechanisms for T cell accumulation in the airways of asthmatics under the influence of specific allergen. These studies will identity potential mechanisms for T cell cytokine circuits in the perpetuation of chronic airways inflammation in asthma.