Immunodeficient scid/scid (scid) mice reconstituted with CD4+CD45RB/high T cells from the lymph node and spleen of normal mice develop a severe T- cell mediated inflammation of their intestine over the course of 4-6 weeks. This cell-transfer model is a powerful experimental system for the analysis of the molecular basis of T-cell mediated inflammation in the gut, because it allows the transfer of donor populations selected on the basis of phenotype or specificity, and the detailed analysis of events both before and during the pathogenesis in the host. Transgenic and other techniques can be used to modify the scid recipients as well. Using this model system, we intend to analyze some of the factors that drive homing to and expansion of pathogenic T-cells into the intestine of recipient scid mice. The major questions include the following: 1. Can we use activation markers and mucosal-specific integrins as more precise markers for T-cells that cause disease? Is prior activation important for homing to the intestine and pathogenesis? 2. Are gut flora required for pathogenesis? If so, are they required to provide antigen for specific recognition by pathogenic T-cells, or do they provide a """"""""conditioning"""""""" factor that permits colonization of the mucosae? 3. Is T-cell activation the intestine sufficient for pathogenesis? Alternatively, are mucosal T- cells anergic and down regulated, and therefore must there be a source of activated, circulating T-cells in the periphery? 4. What is the role of stimulation by specific antigen in pathogenesis of inflammatory disease in scid mice? Are antigen-specific cells required, or does the gut microenvironment stimulate production of proinflammatory cytokines by whatever T-cells happen to be located there? If specific antigen stimulation is required, must it be bacterial? Can the antigen be located in the periphery, in the intestinal mucosae, or must it be in both places? In the proposed studies, we will focus on the earliest immune mediated events related to pathogenesis in this exciting new model for colitis, including T-cell homing, T-cell antigen recognition and T-cell activation. Although we do not assert that the scid transfer model replicates all the features of human IBD, which itself is heterogeneous, we believe that the proposed experiments will shed light on the factors which determine T-cell migration into the intestine, T-cell activation and T-cell mediated pathogenesis, processes that we believe are likely to be critical for the initiation of Crohn's disease and ulcerative colitis.
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