The overall goal of the Program Project is to characterize the role of intestinal immune and inflammatory responses as it effects the hosts' interaction with it's external environment containing antigens, bacteria (toxins) and other microbes encountered at the intestinal mucosal surface. The collective effort of individual research projects in this renewal application has been narrowed to focus on the role of gut epithelium in intestinal barrier function and on the interactions of lymphoid elements (neutrophils, lymphocytes and mast cells) and their cytokines in influencing the epithelial barrier response to luminal stimuli. Within the central theme, the Program Project examines the hosts' response to protein antigens as they influence oral tolerance, host interaction with micro-organisms and consequent epithelial- neutrophil dynamic particularly PMN defensins affect on intestinal secretion and finally with mast cell cytokines effects on these processes, the transport of IgA and Paneth cell release of cryptdins. The program consists of 5 individual projects and 2 Cores and brings together investigators with substantial expertise in immunology, molecular biology, cell biology and microbiology from three departments to accomplish the program's major objective. Individual Project 1 will study the mechanisms of oral tolerance to antigens crossing the gut epithelium by examining antigen presentation by a human enterocyte cell line and specific T cell responses to presentation u sing a TCR transgenic mouse model. Project 2 is an extension of a very productive cell biologic approach to inflammation involving neutrophils and epithelial secretory response to their defensins. Project 3 examines the effect of mast cell cytokines, particularly TNF-alpha, on the recruitment of inflammatory cells and their role in epithelial cell responses. Project 4 is a new project which examines cellular mechanisms of secretory IgA and IgM transport across enterocyte. Project 5, another new project, examines the Paneth cell in intestinal host defense by characterizing, at the molecular level, cryptdin secretion and response to cytokines. Two Core facilities in the area of tissue culture, and administrative services will be located in the Mucosal Immunology Laboratories at MGH-East and have been specifically designed to support the individual investigators and to foster maximum interaction among Program Project participants. The Program Project thus far has provided significant insight into the mechanisms important to intestinal disease and should continue to provide new interaction and new strategies for the prevention and treatment of intestinal disease.
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