T-CELL CYTOKINE/ADHESION MOLECULE REGULATION IN ASTHMA

鉴定T细胞作为主要IgE的控制者 调节开关，通过它们直接与B细胞相互作用，并通过 可溶性细胞因子白细胞介素-4（IL-4）的阐述以及 最近确定的体内作用的CD 4 +T辅助细胞， 哮喘的产生使T细胞的功能在反应中， 哮喘气道中的肛周过敏原或暴露过敏原是一个关键因素， 问题. 该提案的具体目标是， 参与独特细胞因子基因的转录活性因子 激活，特别是IL-4，在T细胞水平，并延长这些 具体的目的是检查这些差异表达 T细胞调节因子在T细胞克隆系中的作用 哮喘家族 将尝试将以下描述与 这些新的因素在遗传水平上与哮喘易感性有关。 Specific Aim 1识别和表征转录因子 T细胞中IL-4基因激活所必需的。 在这些实验中，我们 将评估和表征蛋白质因子提取的细胞核 变应原特异性T细胞系以及变应原特异性T细胞克隆 影响IL-4基因转录的能力。 这些蛋白质提取物结合启动子片段基序， 发现其在调节IL-4活化中是重要的。 我们将 纯化并最终测序和克隆负责这些的基因， 转录因子和开发试剂来研究它们的表达 在不同的情况下。 在具体目标2将审查 先前鉴定的IL-4转录因子的表达 通过特应性T细胞系和克隆的使用。 一项关于 通过这些过敏原触发的细胞选择IL-4和IL-5的使用将 因为这些因素可以识别特应性的风险因素， 和哮喘。 在具体目标3中，我们将研究 受影响的过敏原衍生的T细胞中的转录因子， 在IgE升高和哮喘的家族中未受影响的个体。 在这个特定的目标，实验提出了详细检查T 细胞系转录因子的表达 未受影响的和受影响的家族成员与过敏性和哮喘， 长期在国家犹太人。 将对激活进行分析 这些过敏原特异性反应的特征和差异， 控制T细胞，并试图将这些发现与 在一个庞大的哮喘家族中， 就这么定了 最后，在具体目标4中，我们将研究过敏原驱动的 气道和外周血T细胞粘附分子的表达 哮喘 这些研究对于评估 哮喘患者气道中T细胞聚集的机制 特异性过敏原的影响。 这些研究将确定潜在的 T细胞细胞因子回路在慢性淋巴细胞白血病持续中的作用机制 哮喘中的气道炎症

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.