Aberrant immune responses against antigens derived from resident intestinal bacteria are currently believed to contribute to the pathogenesis of inflammatory bowel disease (IBD) in a genetically susceptible host. However, the cell types involved and the specific mechanisms that result in the development of IBD remain poorly defined. Mast cells are well-known contributors to pathogenesis of immune-mediated diseases such as allergy and asthma. They are unique among inflammatory cells in their ability to release pre-stored TNF when stimulated in addition to de novo cytokine production. Intestinal mast cells bear appropriate receptors and are physically located where they can rapidly respond to enteric bacteria that breach the epithelial barrier. We and others have shown that the TNF they release is critical for control of bacterial infections and for stimulation of antigen-specific immune responses. Thus we hypothesize that mast cells and mast cell-derived TNF play a critical role in the induction and perpetuation of IBD. In this study, mast cell-deficient IL-10-/- mice will be created by cross-breeding existing commercially available strains. The susceptibility of these mice to development of colitis will be determined in the presence and absence of reconstitution with adoptively transferred wild type or TNF-deficient mast cells. The effect of mast cell stimulation on development of colitis will be determined directly using mast cell-sufficient IL-10-/- mice. Finally, treatments that inhibit mast cell activity in the gastrointestinal tract will be developed. The results of these studies have direct implications for both prevention and treatment of IBD in humans. If indicated, follow-up studies will be aimed at determining the mechanisms underlying mast cell activity in IBD as well as more rigorous studies of the efficacy of mast cell inhibitors for therapy of established IBD. ? ? ?
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