IBD DISEASE SUBGROUP STRATIFICATION

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DESCRIPTION (Abstract of the Project) Specific genetic alterations and cellular manipulations have been used to generate animal models that express a range of clinical phenotypes with variations in location, type, and intensity of inflammation, and reflect a variety of clinical expressions similar to that seen among patients with Crohn?s disease (CD) and ulcerative colitis (UC). In the animal models tested thus far, commensal bacteria and host/bacterial interactions have been shown to play a critical role in the mucosal inflammatory response. Animals with the same genetic manipulation when raised in different environments manifest variations in the intensity and/or location of inflammation. These models produce a dominant mucosal cytokine profile that responds uniquely to specific cytokine blockade. It has been demonstrated in both CD and UC that marker antibodies can be used to define clinical phenotypes. In UC, the expression of serum pANCA is associated with more severe colitis and a high incidence of chronic pouchitis. In collaboration with Projects 1 and 3, we demonstrated that pANCA and another marker antibody, ASCA, stratify CD into phenotypes of clinical disease behavior and severity. The groups of patients defined by the type and/or combination of these marker antibodies have variable responses to TNF-alpha blockade. Our recent investigations have identified candidate bacterial antigens and demonstrated the ability of these antigens to stimulate an immune response. Three antigens cross-reacting with pANCA, and 1 identified by RDA can be used to define T-cell responses and associated clinical manifestations. Studies in this project are based on the hypothesis that marker antibody expression and level thereof define specific mucosal cytokine repertoires. Marker antibodies are expected to be associated with distinct T-cell responses to different commensal bacterial antigens known to cross-react with these antibodies. It is also expected that the immune responses are associated with characteristic clinical expressions within UC and CD and that cytokine manipulation or diminution of bacterial antigenic load will regulate inflammation in subsets of patients defined by these immune responses. We will test this hypothesis in studies of UC and CS. First, we will define the relationship of marker and bacteria reactive antigens to T cell proliferation and cytokine secretion in clinically defined subsets of patients. In UC, the relationship of immune response to development and prevention of pouchitis will be investigated. In CD, the ability of immune bacterial response to define patients who will respond best to Th1 cytokine inhibition and/or lumenal bacterial diminution will be investigated.