Inflammatory bowel disease (IBD) is a chronic and relapsing disease of unknown etiology. The regulatory and environmental events that modulate inflammation or trigger a new round of symptoms are completely uncharacterized. The majority of information about factors which perpetuate inflammation in IBD is obtained from chronically inflamed human tissue, while the data from animal models of IBD derives overwhelmingly from early immune responses. In this project we propose to bridge that gap by contrasting the regulation and expression of inflammatory mediators by mucosal immune cells during early and late enterocolitis in murine models. In a healthy individual exposure to a pathogen results in a highly regulated immune response that first clears the organism and then returns to a controlled state. It is our premise that the chronic inflammation observed in ulcerative colitis and Crohn's disease results from an inability of the mucosal immune response to return to this controlled state. Thus, we present the following central hypothesis: Inflammation in experimental murine models of IBD is initiated by mucosal T cell responses to enterobacterial antigens, and it is perpetuated during the late chronic phase by a pro-inflammatory response maintained by mucosal immune and non-immune cells. A corollary of this hypothesis is that the immune response generated in early IBD and toward an infectious pathogen are similar and that the characterize and immune mediator profile of early immunity is distinct from the immune response that causes chronic inflammation. In support of this premise we have demonstrated in a T cell-dependent animal model of enterocolitis (i.e., the IL-10 deficient (IL-10-/-) strain of mice) that the mucosal cytokine profile and anti-cytokine therapeutic efficacy are remarkably different during the early and late phases of intestinal inflammation. We will test this hypothesis with four specific aims: (1) Define the molecular events that regulate mucosal synthesis of IL-12 and IFN-gamma in the early phase of experimental colitis in IL-10-/- mice; 2) Characterize the inflammatory mediators that down-regulate IL-12 synthesis and orchestrate the transition to the late phase of gut inflammation; (3) Investigate the ability of commensal bacterial flora, in general, and Helicobacter species, in particular, to initiate and sustain inflammation in early and late disease; and (4) Identify components of the immune response that support the chronicity of inflammation in the absence of IL- 12 and IFN-gamma production.
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