T Cell Expansion and Colitis in Immunodeficient Mice

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are disorders of the gastrointestinal tract typically characterized by immune-mediated chronic inflammation of the intestines, especially of the colon. Although multiple factors contribute to the etiology of IBDs, it is becoming increasingly clear that the main cause of the diseases is dysregulated chronic T cell responses to the antigens of the commensal bacteria. One simple and useful mouse model of IBD is the system of adoptively transferring small numbers of naive CD4 cells into syngeneic immunodeficient mice. In this system, host ARC loaded with commensal bacterial antigens are believed to induce the donor CD4 cells to undergo strong activation and differentiation into effector T cells that secrete inflammatory cytokines in the intestines. Strikingly, the disease in this system can be efficiently prevented by co-injecting regulatory T cells (Treg). Although the mechanisms of how Treg prevent the disease are being better defined, many other aspects of the model are yet to be clearly defined. To better understand some of these issues, the following three areas of investigation are proposed. First, the factors that drive the activation of donor naive CD4 cells will be better defined. Second, the factors that induce activation and expansion of Treg necessary for prevention of colitis will be defined. Third, cellular mechanisms involved in regulating potentially pathogenic CD4 cells will be better defined. Results from these investigations may be useful in designing better approaches for preventing or treating IBDs in humans.