Inflammatory bowel disease probably is an immunological disorder resulting from both genetic and environmental factors. The principal investigator has on hand three murine models in which the mice spontaneously develop inflammatory bowel disease because of immune dysregulation. The main hypothesis of this proposal is that, in genetically susceptible animals, bacteria drive macrophages to induce activated CD4+ TH1 cells through IL-12 dependent mechanisms. It also is proposed that T cell migration to the lamina propria is important for the development of experimental colitis. The two major models to be employed include the C57CD45Rbhi into Ragnull mice model and the BMT into tg epsilon 26 animal model. The project has four specific aims that will use transgenic animals, neutralizing antibodies and adoptive cell transfer to study intestinal immunoregulation. 1.) The project will ascertain the importance IL-12 and its dependent pathways for the development of intestinal inflammation. 2.) Experiments will explore the importance IFN gamma, IL-15 and CD40L/CD40 interaction in the regulation of experimental colitis. 3.) Other experiments will study the importance of intestinal bacteria for the induction and maintenance of inflammation in transgenic mice. 4.) The final aim is to explore the role of alpha 4 integrin in the recruitment of regulatory T cells to intestinal inflammation. The project is supported by extensive preliminary data.
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