ANTI-BACTERIAL MUCOSAL IMMUNE RESPONSES IN HUMAN IBD

Cedars-Sinai Medical Center, West Hollywood CA

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Abstract

Accumulating evidence implicates a significant contribution of intestinal bacteria in IBD pathogenesis. We hypothesize that an antigen-specific immune activation by bacterially expressed proteins mediates the aberrant immune response in the inflamed mucosa. Accordingly, the overall goal of this proposal is to define the antigenic target of the immune response in IBD. Our group recently identified E. coli OmpC, Bacteroides OmpW, and Mycobacterial HupB as candidate targets for the pathogenic immune response underlying human IBD, using the UC associated marker antibody, pANCA. Here, we propose to evaluate these candidate pANCA antigens as targets for a mucosal T cell response in the IBD gut. Aim I will correlate the mucosal T cell response to candidate antigens with serum pANCA levels in an IBD patient cohort. Aim 2 will evaluate T cell responses in relation with disease activity or location. Primary T lymphocytes from lamina propria or peripheral blood T will be isolated and co-cultured with antigen-pulsed autologous antigen presenting cells (APC). Proliferation as well as activation marker expression and cytokine secretion profiles will be assessed as an indication of antigen specific response. For a more refined analysis of a response, we will rigorously analyze the cytokine secretion profiles to ascertain the nature of the identified T cell specificity in the context of Th1 vs. Th2 or suppressor cell response. Reactivity profiles across a broad UC patient cohort will be statistically analyzed for correlation between antigen specificity and serum pANCA levels or disease- state. Findings from this investigation will define a patient subset expressing a pANCA-related T cell response, and will characterize the pANCA reactive T cell population. In addition, specific microorganisms involved in UC pathogenesis may be identified. And finally, at the molecular level, this study will determine which of the suggested pANCA reactive proteins constitutes a significant antigenic target of the mucosal immune compartment in human IBD.