Specificity and mechanisms of lung lymphocyte homing

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DESCRIPTION (provided by applicant): Asthma affects approximately 20% of children and 5% of adults in the western world. Marked by chronic inflammation of the airway tract, asthma is mediated by pro-inflammatory proteins, including cytokines, chemokines and adhesion molecules. Inhibitors of trafficking molecules are emerging as new therapeutic avenues for the treatment of immune diseases. Clarifying the mechanism of T cell homing to the lung and the role of lung lymphocyte-expressed receptors could delineate potential targets for the treatment of asthma and other pulmonary inflammatory diseases. This proposal aims to test whether a specific mechanism of pulmonary lymphocyte homing to lung exists and to identify the adhesion and chemoattractant receptors involved. On the basis of published studies, a mechanism of lung-selective migration of lymphocytes has been implicated. However, whether the pathway for pulmonary T cell homing to the lung is specific and distinct from skin- or gut-homing is not known. Using mouse models and in vivo migration assays that we have developed, we will first formally test whether pulmonary memory T cells preferentially migrate back to the lung, as compared with the lung- and other tissue-homing of cells from other systemic organs and lymphoid tissues. In addition, by applying established immunohistochemistry techniques, we will identify the micro-environment or compartments of the lung to which the homed cells localize. Second, to determine the molecular players involved, we will use flow cytometry and blocking antibodies in in vivo migration assays to test the involvement of specifc endothelial and lymphocyte adhesion receptors. Chemoattractant receptors are known to regulate the migration of lymphocytes from the blood stream to sites of immune responses. Our preliminary gene expression analyses consistently identified the lung-selective expression of two putative chemoattractant receptors. Using mouse models of gene knockout and wildtype controls, we will lastly determine the expression profile of these receptors on ymphocyte subpopulations. Importantly, to understand whether these novel receptors play a role in lung homing, we will also test how the deficiency of these receptors in the knockout animals affect the lung homing of pulmonary lymphocytes. Relevance: The goal of this research proposal is to determine whether lung homing is selective and to elucidate the underlying mechanisms. Information gained from this research can be applied towards developing inhibitors of the contributing proteins for the treatment of asthma or other lung inflammatory diseases.