Peribronchial leukocyte accumulation and activation is a major disease factor during development of asthmatic airway responses that leads to chronic airway disease. In particular, lymphocytes and eosinophils have been reported to be primary populations associated with induction of bronchial injury, and are thought to participate in bronchial obstruction and airway hyperreactivity. Our investigations of the allergic airway response have identified chemokine receptors that are upregulated during the allergen-induced response within the airway. In particular, the expression of CCR6 appears to correlate with disease development within our model of cockroach allergen-induced disease and deletion of this protein significantly attenuates the pathophysiology. Our data suggest that this chemokine receptor plays critical roles in the allergic response, both for localization of T lymphocytes and for activation of the cells within the draining lymph nodes of the lung. Our hypothesis is that CCR6 and its ligand, CCL20, have multiple roles in the development of the pathophysiologic airway responses during allergen-specific activation involving both T lymphocytes and dendritic cells (DC). We will utilize a series of specific experiments designed to identify the mechanism(s) of recruitment and activation of T lymphocytes and dendritic cells during the development of the allergen-induced disease. Our studies will address important questions to identify the basic mechanisms involved in these processes including, 1) What lymphocyte populations express CCR6 and are they important for the development of the allergic responses within the airways and/or activation within the lymph nodes? 2) Does the expression of the CCR6 ligand CCL20 correspond to the localization of lymphocytes and dendritic cells during the allergic response? 3) Is the defect of CCR6 deletion centered on lymph node and/or lung localization of T lymphocytes? 4) Does CCR6 expression on dendritic cells have a contributing role of the developing allergic airway disease? 5) Does activation of DCs or lymphocytes via CCR6 impact directly on the immune phenotype of the response? 6) What is the expression pattern and in vivo function of CCL20 for development of the allergen-induced airway responses? Together, addressing these questions will allow us to outline the mechanisms involved in this complex inflammatory response using adoptive transfer and gene deletion technology. In addition, we will utilize cells from GFP expressing mice and CFSE labeled cells to allow analysis of trafficking of cells that have been transferred in vivo. The proposal identifies that the complexity of these responses appears to involve both T cells and DC that express CCR6 and are required for the full activation of the allergen-driven responses.
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