Ulcerative colitis and Crohn's disease, collectively referred to as inflammatory bowel disease (IBD), are chronic, spontaneously relapsing disorders, which appear to be immunologically mediated and to have genetic and environmental components. The pathways that lead to these diseases were in principle dissected by using genetically well-defined animal models. The main objective of this proposal is to begin to translate the principles that the PI and others have established in studies of animal models to the human IBD. The major hypothesis is that two possible mechanisms exist for the presence of """"""""Aggressor Th1 cells"""""""" in experimental colitis and therefore in human IBD. In one model the Polarized Th1 cells that are found in the lamina propria are induced to become aggressor Th1. In an alternative model the absence of regulatory cells (for instance Th1 cells, but not per exclusion of others) leads to the generation of the aggressor Tr1 cell. The two models most likely cooperate in the induction of pathogenesis of IBD. In this proposal the investigators seek to further dissect these functional subsets of human LPLs based upon two major hypotheses: (1) unique subsets of T lymphocytes exist within the LPL compartment these include regulatory T cells such as Tr1 cells; and (2) the function and frequency of regulatory T cells (Trl and CDld reactive NKT cells) is perturbed in IBD patients. We specifically proposes to: (1) define the role of SLAM/SAP system in controlling induction of IFN-gamma, IL-10 and TGF-beta genes by lamina propria lymphocytes; (2) test the hypothesis that human Tr1 cells regulate immune responses by lamina propria T lymphocytes from normal individuals, but not in patients with Ulcerative Colitis or Crohn's disease; and (3) test the hypothesis that human CD1-d reactive T cells regulate immune responses by lamina propria T lymphocytes, but not in patients with Ulcerative Colitis or Crohn's disease.
