Affiliations Center for the Study of Inflammatory Bowel Disease
Center for the Study of Inflammatory Bowel Disease
Atul K. Bhan, MBBS, MD
Massachusetts General Hospital
Professor of Pathology
Harvard Medical School
In the two major forms of inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis the underlying etiological factors and the pathogenesis remain poorly defined. It is generally believed that exaggerated immune responses to luminal normal enteric flora are involved in the initiation and perpetuation of the disease process. The recent availability of a wide variety of experimental models of intestinal inflammation has helped provide important clues about the pathogenesis of IBD. The commonly used models include chemically induced mucosal injury and colitis induced by the transfer of selected populations of T cells into immunodeficient mice. The spontaneous development of colitis in genetically engineered animal models, including T cell receptor (TCR) alpha KO mice, and mice deficient in IL-2, IL-10, and the Wiskott-Aldrich syndrome protein (WASP) have provided excellent experimental models to study the pathogenesis of IBD. One important lesson learned from IBD models is that many different immunologic and mucosal defects can lead to similar pathologic findings.
The laboratory is closely associated with the Center for the Study of Inflammatory Bowel Disease at the MGH and collaborates with the other members of the Center; Dr. Bhan is an Associate Director of the Center. In collaboration with Dr. Cox Terhorst's laboratory we have studied the pathogenesis of Th-1 mediated models of colitis in CD45RBhigh transfer model and bone marrow transplanted CD3εtg mice. In both models, colitis develops due to lack of T cell regulation. Collaborative studies with Dr. Scott Snapper’s laboratory indicate that WASP protein is required for the function of regulatory CD4+, CD25+Foxp3+ T cells.
Atul K. Bhan, MBBS, MD
For the last several years, our laboratory has focused on defining the pathogenesis of chronic intestinal inflammation using TCR alpha KO mice as a model of human IBD. TCR alpha KO mice develop spontaneously chronic colitis with many features of ulcerative colitis. These features include restriction of inflammation to the colon and the mucosa, presence of autoantibodies, the protective role of appendectomy and pathogenic role of Th-2 pathway in the development of colitis. We have identified a regulatory B cell subset, which appears under chronic intestinal inflammatory conditions and suppresses the progression of intestinal inflammation by secreting IL-10. Recently, we have identified an IL-12-producing regulatory B cell subset. TCR alpha KO mice deficient in both IL-4 and B cells, but not in IL-4 alone, develop granulomatous colitis with features of Crohn’s disease. This suggests that differences in the two major forms of IBD may reflect different immunological responses to similar initiating events.