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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064586-05
Application #
7559988
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Rothermel, Annette L
Project Start
2005-05-15
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$440,665
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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