Histamine and other inflammatory mediators that are released by crosslinking the high affinity IgE receptor, FceRI, of mast cells and basophils contribute to the bronchial constriction and mucus secretion found in asthma, while mast cell and basophil-derived Th2 cytokines contribute, with T cell-derived cytokines, to the recruitment of eosinophils to the lung and to the maintenance of a lung microenvironment that influences allergen-bearing lung dendritic cells to continuously drive non-committed T cells to the Th2 subset. The guiding hypothesis of this Project is that understanding and modulating the FceRI- mediated signaling pathways of human basophils and mast cells will yield new strategies to reduce the active symptoms and immunological progression of allergic asthma Our recent work has linked the failure of basophil FceRI signaling in a minority of blood donors (""""""""non-releasers"""""""") to a reversible loss of the FceRI- coupled tyrosine kinase, Syk, in basophils but not in other blood leukocytes. In the renewal period, continuing work will establish if having Syk-deficient basophils is protective against asthma, if Syk is absent from lung mast cells obtained by bronchial biopsy from donors with non-releaser basophils and if reconstituting Syk restores FceRI signaling in non-releaser basophils. Mechanistic studies will test the hypothesis that the basophil Syk deficiency results from increased Syk degradation by the ubiquitin-proteasome pathway, possibly linked to Cbl, a Syk-binding adaptor protein with E3 ubiquitin kinase activity. Gene expression differences between Syk- and Syk+ basophils will be discovered by microarray analysis. Genentech scientists have provided us with their recombinant humanized anti-IgE mAb, rhumAb-E25, a new therapeutic agent that was designed to reduce circulating IgE levels but proved additionally to suppress basophil FceRI expression and signaling. In the renewal period, we will determine if rhumAb-E25 treatment reduces FceRI expression and FceRI signaling in the lung mast cells of mild asthmatics. Mechanistic studies will test the hypothesis that IgE removal reduces FceRI stability and FceRI-kinase coupling. These integrated fimdamental and clinical studies are expected to provide new basic understanding of FceRI signaling pathways, new insight into the contributions of basophils and mast cells to allergic disease, and new therapeutic strategies for asthma.
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