Role of the IL-23/IL-17 axis in Inflammatory Bowel Disease. (360G-Wellcome-080667_Z_06_Z)

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC). Experimental and clinical studies suggest that IL-12 plays a role in CD via promotion of Th1 cells and increased IFN-g and TNF-a. IL-23 is a novel member of the IL-12 cytokine family. While IL-12 drives the classical Th1 response, IL-23 promotes the expansion of a T cell population characterized by IL-17 and IL-6 production. In recent studies in mouse models of IBD we have uncovered differential roles for IL-12 and IL-23 in the systemic and mucosal immune response. While IL-12 was found to drive systemicimmune pathology, T cell-independent intestinal inflammation was dependent on IL-23 and not IL-12. These results also suggested that IL-23 drives the production of a novel population of IL-17 producing innate immune cells. The aim of this project is to elucidate the role of IL-23/IL-17 pathway in IBD andfurthermore to determine the cellular source of these cytokines and mechanismsinvolved in their regulation. Alterations in NOD2, a bacterial sensing proteinconfer susceptibility to CD in a subset of patients. We will investigate whether individuals expressing mutant NOD2 proteins have alterations in the IL-23/IL-17 axis.