and/or aims) The goal of this proposal is to delineate the alterations in cell-mediated immune function which initiate and/or perpetuate IBD. The focus will be on mechanisms and significance of altered human intestinal immunoglobulin expression in IBD as assessed (1) in vitro by isolated IBD intestinal lamina propria mononuclear cells, (2) in situ in IBD intestinal tissue sections, and (3) in vivo in IBD serum. The working hypothesis is that mucosal cell- mediated immunity in general, and intestinal immunoglobulins in particular, participate in IBD by providing the central mechanism that facilitates the transition from initiating to effector events. Four basic specific aims will be pursued: (1) characterization of the immunogluobulins present in and secreted by control and IBD intestinal mononuclear cells, by evaluation of isolated cells for cytoplasmatic and cell surface immunoglobulins, examination of antigenic specificity of antibodies in IBD, studies of Fc receptor binding and cell activation and determination of restricted clonality of secreted antibodies; (2) delineation of alterations in receptors of intestinal lamina propria mononuclear cells in IBD, by examining IBD cells for functional binding to high endothelial cells in IBD, by examining IBD cell for functional binding to high endothelial venules, and fluorescent activated cell sorter (FACS) examination of IBD intestinal cells for cell surface homing receptors; (3) evaluation of the state of activation of isolated IBD intestinal mononuclear cells, by examining IBD intestinal cells for the presence of cell surface activation markers; (4) assessment of mediators of inflammation, cytokines, inhibitors of the lipoxygenase pathway and drugs used in the therapy of IBD as moculators of antibody secretion, by examining drugs used in the treatment of IBD, the effect of cytokines on IBD intestinal B cell activation and maturation, and evaluating the effects of arachidonate metabolites on antibody synthesis and secretion.
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