The major objectives of this program are to probe intestinal host defense against the external environment, with special emphasis on selected aspects of local and systemic immunologic function and dysfunction as they pertain to manifestations of intestinal and systemic disease. The project is directed toward expanding the characterization of the gut as an immunologic organ and its relationship to other components of the immune system. Major areas of investigation will include the following: (1) A detailed study to characterize the development of mucosal barrier function in the human fetus and newborn including characterization of enterocyte receptors for bacterial exotoxins and growth factors with respect to the role of glycosylation in receptor function, characterization of an identified """"""""Fc: receptor on the fetal enterocyte and a detailed study of the ontogeny of mucosal lymphocyte cellular functions. (2) In this project, an animal model will be utilized to examine potential interactions between dietary antigens and milk cells in influencing the neonate's developing immune system. The hypotheses to be tested are: a) that milk cells transport, process, and present dietary protein antigen to the neonate's intestinal epithelium and mucosal immune system; and b) that exposure of milk cells to dietary proteins or protein fragments alter their """"""""functional"""""""" state and production cytokines. (3) this project will continue the study of experimental allergic gastroenteropathy. This includes a study of the renal clearance of absorbed intestinal food protein fragments, defining the role of bystander antigen in intestinal anaphylaxis, transfer of dietary antigen across the stomach in mast cell deficient rats, deposition of food antigen-antibody complexes in the serum of allergic rats, and finally, to determine the role of platelet activating factor in the allergic gastroenteropathy model. (4) these experiments are designed to probe the effects on intestinal epithelial structure and function of interaction between polymorphonuclear leukocytes (PMN) and intestinal epithelial cells. (5) the major goal of the project is to define the antigens associated with intestinal mucosal lymphocytes; these antigens play an important role in the compartmentalization and function of these cells at the mucosal sites. (6) the aim of this project is to define the unique contribution of mast cells to IgE-dependent reactions occurring in the stomach utilizing a new model system recently developed by the investigators to analyze gastric mast cell function. (7) The goal of this project is to study two complementary aspects of GI tract enterobacterial infections. The first sub-project concern the identification of E. coli K1 genes that are specifically required for blood stream survival. The second sub-project concerns extraintestinal immunological manifestations following infection with yersinia enterocolitica. This will be done by utilizing the yersinia TSH receptor-like protein as a model for studying enterobacterial infection and antigen presentation in the gut, and its role in autoimmune disease. Three core facilities, including a flow cytometry and molecular biology core, will be used to support these projects.
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