The atopic diseases consist of the triad of asthma, allergic rhinitis, and atopic dermatitis. These diseases share a common pathogenesis, involving inflammatory Th2-type cytokines and elevated IgE. These data suggest that these diseases share a common initiating factor. However, the nature of this initiating factor remains to be determined. One possible candidate for a factor involved in the initiation of allergic inflammatory responses is the cytokine thymic stromal lymphopoietin (TSLP). TSLP is expressed by epithelial cells, with the highest levels seen in lung and skin-derived epithelial cells. Studies using human CD11c+ dendritic cells showed that these cells produced CCL17 and CCL22, chemokines capable of attracting Th2-type CD4+ T cells. In addition, when CD4+ T cells are primed on TSLP-treated DCs they take on an inflammatory Th2 phenotype, producing IL-4, IL-5, IL-13, and TNF-cc upon restimulation. Finally, lesional skin, but not unaffected skin, from patients with atopic dermatitis expresses high levels of TSLP. These data suggest a role for TSLP in the initiating events in atopic dermatitis, one leg of the atopic triad. To begin to assess a possible role for TSLP in other atopic diseases we have developed animal models using a tissue-specific TSLP transgene. We have shown that expression of TSLP exclusively in the lungs of transgenic mice causes airways inflammation, exemplified by a leukocytic infiltrations that includes Th2-type T cells, hypertrophy of the epithelium and subepithelial fibrosis, goblet cell hyperplasia and mucus overproduction, and markedly elevated levels of IgE. In addition, mice that lack the TSLP receptor have a dramatically attenuated disease response in a model of antigen-driven asthma. Thus, TSLP is both necessary and sufficient for the development of airway inflammatory disease. This proposal will extend those results by determining the roles played by the various infiltrating cell populations in TSLP-mediated disease, as well as the function of the Th2 cytokines IL-4 and IL-13 in the disease process. We will also determine whether TSLP blockade is efficacious in treating ongoing disease. The data generated by these experiments will allow for a determination of the role of TSLP in airway inflammation, and will provide the model systems to test the therapeutic efficacy of TSLP interdiction. ? ? ?
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