Asthma is a disease of airway inflammation resulting from an allergic type reaction to an inhaled environmental antigen. CD4+ T helper type 2 (Th2) cells play a critical role in initiating and propagating this allergic inflammation, as elevated levels of IL-4, IL-5 and IL-13 are found in airways of asthmatics, where they drive this pathologic response. Adoptive transfer of effector Th2 cells into naive mice followed by exposure to inhaled antigen induces the pathophysiologic features of asthma, including eosinophilic inflammation, mucus hypersecretion and airway hyperreactivity, demonstrating that Th2 cells are fully capable of producing the asthma phenotype. While it is firmly established that Th2 cells are central to the pathogenesis of asthma, the molecular mechanisms controlling antigen-induced Th2 cell trafficking into the allergic lung are unknown. The long-term objective of this grant is to identify the key chemokines/chemoattractant receptors that control the recruitment of Th2 cells into the allergic lung and to determine the mechanisms regulating the production of these chemokines active on Th2 cells and eosinophils in allergic inflammation. In this application, we specifically propose: 1) To determine the relevant chemokine/chemoattractant receptors responsible for Th2 cell trafficking to the allergic lung using adoptive transfer of chemokine/chemoattractant receptor deficient effector Th2 cells in the murine model of allergic pulmonary inflammation; 2) To identify the critical cytokines that stimulate the production of chemokines active on Th2 cells from human epithelial and endothelial cells in vitro and to define the key parenchymal cell type(s) in the lung that mediate chemokine production; 3) To define the regions in chemokine promoters that regulate the induction of chemokines by cytokines and to determine the transcription factors that mediate their induction; 4) To determine the chemokine receptor profile on T cells recruited into human airways following aerosol antigen challenge of atopic patients with and without asthma using flow cytometry.
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