Recent studies implicate the lymphocyte integrin alpha4Beta7 as a 'homing receptor' for the mucosal vascular addressin MAdCAM-1, a vascular Ig- family member that defines sites of lymphocyte extravasation into mucosal microenvironments. Our overall goal is to define the importance of alpha4Beta7 in the pathology and physiology of mucosal immunity and inflammation, and its role in the systemic segregation of mucosal from nonmucosal immune systems.
Specific Aims i nclude: 1) To determine if alpha4Beta7 expression by lymphocyte subsets correlates with and predicts their binding to MAdCAM-1, and their in vivo trafficking to mucosal tissues and to inflamed gut in models of intestinal inflammatory disease. Adhesion of circulating lymphocytes to MAdCAM-1 (and for comparison to VCAM-1) will be correlated with lineage, memory vs. naive phenotype, and expression of alpha4Beta7 (vs alpha4Beta1). Animal models will be used to measure the capacity of alpha4Beta7hi vs. alpha4Beta7 memory cells to home to and recirculate through mucosal vs. peripheral tissues. 2) To test the hypothesis that alpha4Beta7hi CD45R0+ T cells comprise T cell memory for intestinal recall antigens: Human PBL will be FACS sorted to isolate CD45RA-CD4+ 'memory' T cells of presumptive mucosal (alpha4Beta7hi) vs. nonmucosal (alpha4Beta7-) phenotypes, and each fraction will be assayed in vitro for recall responses to the ubiquitous intestinal pathogen rotavirus. 3) In situ videomicroscopy will be used to analyze directly the role of alpha4Beta7 in lymphocyte attachment, rolling and activation-dependent arrest in Peyer's patch-high endothelial venules (HEV); and in the venules of the small intestinal lamina propria. These in vivo studies are critical to understanding the mechanism by which alpha4Beta7 regulates lymphocyte trafficking to mucosal sites in conjunction with other adhesion and activating receptors. 4) Immunohistologic and flow cytometric approaches will be used to study the regulation of alpha4Beta7 during ontogeny and lymphocyte differentiation; and in chronic inflammation in mucosal vs. other tissues, especially in inflammatory bowel disease in man, or in intestinal inflammatory models in mice. 5) MAb and peptide inhibition studies will be carried out to determine whether alpha4Beta7 recognition of its known ligands (MAdCAM-1, VCAM-1, fibronectin), and alpha4Beta7 participation in lymphocyte aggregation, involve distinct or overlapping integrin epitopes or peptide binding pockets. 6) Lymphocyte binding to immunoisolated alpha4 monomer and to alpha4-derived peptides will be assayed to determine the ability of the alpha4 integrin chain to serve as a substrate for alpha4Beta7 (and alpha4Beta7) adhesion, and to define the peptide sequences involved. Functional studies of transfectants expressing mutated alpha4 will assess its role as a ligand in lymphocyte aggregation and in immune cell interactions. Taken together, the proposed studies should help define the roles of alpha4Beta7 in mucosal lymphocyte trafficking and immune responses, and in pathologic inflammatory diseases. They may lead to novel approaches to regulating pathologic immune and inflammatory reactions in inflammatory bowel disease.
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