T cells regulate inflammatory responses in the intestine. The adhesion molecule integrin alpha4beta7 plays a crucial role in controlling T cell migration to the intestine by binding to MAdCAM-1, which is expressed on Peyer's patch high endothelial venules (HEV) and lamina propria venules. Antibodies against alpha4beta7 and MAdCAM-1 have impressive therapeutic effects in animal models of inflammatory bowel disease. The objective of this project is to understand the role of alpha4beta7 in the regulation of intestinal immunity and inflammation. This revised proposal more fully addresses the clinical relevance of the work by incorporating additional in vivo mouse studies and studies of human intestinal lymphocytes. There am three specific aims.
Aim 1 is to analyze how chemokines regulate alpha4beta7-mediated adhesion to MAdCAM-1. We found that HEV produce a novel chemokine, SLC, that rapidly activates alpha4beta7. We will investigate the effects of other potentially relevant chemokines on alpha4beta7-mediated adhesion. We will also determine whether there are increases in the production of SLC and other lymphocyte-specific chemokines that might account for T cell accumulation during intestinal inflammation.
Aim 2 is to analyze the relationship between Th1/Th2 polarization, alpha4beta7 expression, and migration of CD4+ T cells to the intestine. We found that Th1-promoting conditions lead to higher expression of alpha4beta7 in vitro. We will determine how Th1/Th2 differentiation affects alpha4beta7 expression and function in vitro and in vivo. We will also determine the relationship between alpha4beta7 expression and production of Th1- and Th2-type cytokines using blood and intestinal T cells from normal subjects and subjects with inflammatory bowel disease.
Aim 3 is to analyze the effects of alpha4beta7 engagement on CD4+ T cell proliferation and cytokine production. Antibody against alpha4beta7 inhibited IFN-gamma production by T cells in vitro, suggesting that alpha4beta7 modulates the response of intestinal T cells to their environment. The proposed experiments will investigate the effects of alpha4beta7 binding on cytokine production and T cell proliferation in vitro and in vivo. This project will advance our understanding of the role of alpha4beta7 on T cells and could lead to novel strategies for modulating inflammatory responses in the intestine.
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