This application seeks funding for studies aimed at evaluating how the cytokine MIF and the receptor / counter-receptor pair CD48/CD244 control the innate immune responses involved in the development of experimental colitis. Experiments with MIF -/- mice demonstrated that production of MIF by macrophages is a major factor in the pathogenesis of colitis. Experiments with CD48 -/- mice suggest a role for CD48 on the surface of macrophages, dendritic cells and CD4+ T cells in development of the disease. We will further evaluate the molecular underpinnings of the therapeutic antibodies anti-MIF and anti-CD48. Our general hypothesis is that MIF and the interaction of CD48 with its counter-receptor CD244 govern specific pathways to experimental colitis. The fundamental strategy is to examine the contribution of MIF and CD48 and its ligand CD244 in the pathogenesis of colitis by using monoclonal anti-MIF, -CD48 and -CD244 and adoptive T cell and bone marrow transfers using MIF-/-, conditional MIF-/- and MIF-IRES - GFP reporter mice, as well as CD48-/- and CD244-/- mice. The experiments proposed in this application are grouped in the following specific aims:
Specific Aim#1 : To test the hypothesis that production of the cytokine MIF by intestinal macrophages and neutrophils is a key contributor to experimental colitis.
Specific Aim#2 : To test the hypothesis that the cell surface receptor CD48 governs pathways to colitis involving CD4+ T cell and macrophage interactions.
Specific Aim#3 : To determine the function of the macrophage / neutrophil cell surface receptor CD244, the ligand of CD48, in the pathogenesis of experimental colitis. This application seeks funding for studies using monoclonal antibodies in combination with genetically manipulated mice to elucidate pathways to experimental colitis. The outcomes of the proposed experiments should clarify the mechanisms governed by expression of the cytokine MIF and the receptor / counter structure pair CD48/CD244 in the lamina propria of the colon. These novel insights into the interplay between pathogenic T cells and the innate immune system will not only shed light on the pathogenesis of experimental colitis, the results of these studies should suggest therapeutic strategies that can be applied to IBD patients.
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