Dysregulation of activated T cells leading to a chronic inflammatory state is a central feature of inflammatory boweI disease (ulcerative colitis and Crohn's disease). Co-stimulatory molecules expressed on activated T cells and antigen presenting cells (i.e. macrophages and dendritic ceils) orchestrate T cell((antigen presenting cell interaction and define the type of T cell response (i.e. activation vs. anergy). SLAM (signaling leukocytic activation molecule, CD150) is a co-stimulatory molecule highly expressed on both activated T cells and macrophages. Through augmentation of pro-inflammatory cytokines, SLAM co-stimulation potentiates the inflammatory state. Preliminary data suggest that disruption of SLAM signaling on activated T cells protects against colitis and SLAM deficient (SLAM-/-) macrophages have a profound defect in pro-inflammatory function. Based on this work we generate the novel hypothesis that SLAM co-stimulation is critical to the function of both macrophages and activated T cells that mediate chronic inflammation in colitis.
In specific aim #1, we will use SLAM -/- mice crossed to the Rag-/- background (no T or B cells) to test the hypothesis that SLAM expression on antigen presenting cells is critical to the induction and maintenance of experimental colitis.
In specific aim #2, the potential of SLAM-/- T cells to cause colitis will be studied. The ability of anti-SLAM antibodies to prevent colitis will be tested in vivo in two models of experimental colitis in specific aim #3. The studies will test activation states of different T cell subsets and macrophages in vitro by cytokine assay (ELISA). Assessment of colitis in vivo will be made by clinical parameters (i.e. weight loss, diarrhea) as well as histologic scoring of the colon at autopsy. This work will establish the role for SLAM in the initiation and maintenance of colitis and has the potential of identifying a new therapeutic target for the immune modulation of human inflammatory bowel disease.
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