Despite the fact that the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, have several characteristics consistent with the consequences of macrophage activation, no concerted effort has been made toward defining the specific role of these cells in either the pathogenesis or clinical expression of IBD. Because macrophages are critical components of both primary and secondary immune responses, these cells must be actively involved in the immune processes associated with IBD. We and others, both directly and indirectly, have already documented that macrophage activation is present in these diseases. In this proposal we plan to focus our efforts on defining the macrophage populations that are present in the gastrointestinal tract, both phenotypically and functionally. This will be accomplished by a series of immunohistochemical studies looking at activation and population markers, as well as by assessing the functional properties of these cells once isolated from the intestine. Through the analysis of function and secretion of a number of mediators, we plan to identify model systems that might explain the pathologic and clinical picture of IBD. Emphasis will be placed on T cell activation, monokine secretion resulting in proliferation of fibroblasts and smooth muscle, and macrophage-derived mucus secretagogues which may play an important role in the mucin depletion seen in ulcerative colitis. Once specific macrophage properties are identified, one can approach therapies directed at the consequences of macrophage activation and aid in controlling the inflammatory process.
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