The overall goal of these studies is to better define the pathways leading to infiltration of basophils into allergic reaction sites in humans. Recent studies indicate that the number of basophils migrating into sites of allergic inflammation is substantially greater than previously appreciated and that basophils produce large amounts of IL-4 and IL-13. It is thus imperative that we better understand the mechanism of recruitment of these important cells. The proposal consists of four integrated aims; two involve clinical intervention in human subjects and two involve in vitro studies of basophil recruitment and function. Studies in Aim 1 will identify the chemokines and chemokine receptors that mediate basophil chemotaxis and transendothelial migration. Solid preliminary studies indicate that human basophils express a host of chemokine receptors, including CCR1-3 and CXCR4, and functional data suggest that they may also express additional receptor types. We will complete an ongoing screen of all of the known chemokines and their receptors for the ability to activate basophils. Selectivity of basophil-active chemokines will be determined by assays with eosinophils, neutrophils and mononuclear cells. Studies in Aim 2 will test the hypothesis that basophils contribute to the phenotypic changes observed in epithelial cells during allergic inflammation of the airways. Preliminary results indicate that purified human basophils can activate epithelial production of chemotactic factors. We will study the molecular basis of the interaction of airway epithelial cells and purified human basophils, focusing on the reciprocal activating cytokines produced by each cell type and the requirement for cell contact. Studies in Aim 3 will determine the importance of TNFa in recruitment of basophils by testing the influence of the TNFa antagonist, Enbrel, on the influx of basophils into the skin, the nose and the lung in allergen challenged human subjects. Studies in Aim 4 will determine the spectrum and cellular sources of basophil-activating chemokines produced in experimental allergic reactions using laser capture microdissection and Taqman realtime PCR on samples derived from antigen challenge in human subjects. It is hoped that elucidation of the molecular mechanism of selective basophil recruitment will be the first step in the development of strategies to disrupt this process for therapeutic gain.
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