T-CELL CYTOKINE/ADHESION MOLECULE REGULATION IN ASTHMA

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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.