Inflammatory bowel disease (IBD) are chronic, relapsing, tissue destructive disease. Recent advances in experimental models for IBD in mice have contributed to a better understand of the mechanisms of intestinal inflammation involving dysfunction of T cells and dysregulation of cytokine production. Notably, a central role for interferon-gamma (IFN-gamma) produced by T helper type 1 (Th1)-T cells and for inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been emphasized in these murine models. However, the immunological events which occur in human IBD are not always accommodated by these models. In ulcerative colitis, it is generally recognized that a role for TH1-type responses are not as evident as in Crohn's disease. In our recent investigation, we have obtained evidence that Th2-type responses are also much involved in a murine hapten-induced IBD model which is accompanied by expansion of colonic patches, which are the gut associated lymphoreticular tissues in the colon. Since inflammatory lesions were induced in a condition deficient in Th1 type cells producing IFN-gamma, and were distinct from the lesions seen in mice deficient in Th2 cytokines, we hypothesize that cytokine-phenotypes may explain the different pathological findings in ulcerative colitis and Crohn's disease. The major goal of this grant is to show that Th2-type responses can induce distinct types of lesions from those caused by Th1-type responses. Further, we will define colonic patches as inductive sites of chronic intestinal inflammation that occur through Th2 immune responses. To address this goal, the first aim will be to study the specific roles of Th2-type cells in murine intestinal inflammation through an adoptive transfer system of CD4+ CD45RB/Hi T cells. This study will be done with interactions with project 1 (Dr. Elson) in which adoptive transfer of Th1- or Th2-skewed T cells derived from C3H/HeJBir mice will also be investigated. In the second aim, we will define specific functions for colonic patches by comparing them with Peyer's patches for immune responses to defined antigens and delivery vectors/adjuvants which induced mucosal immunity via Th1- or Th2-type T cells. This study will interact with Project 2 (Dr. Weaver) for studies of antigen (OVA)-specific responses.
The third aim will determine if colonic patches are necessary to induce intestinal inflammation by using mice deficient in organized colonic patches. Finally our last aim will define novel molecules which are specifically expressed in colonic patches using 2 dimensional gel analysis and differential display of mRNA between Peyer's and colonic patches. These latter techniques will also be applied to Project 4 (Dr. Leiter) to compare congenic stocks of mice which are done to develop inflammation. These proposed studies will provide new information for understanding the pathogenesis of non-Th1 type intestinal inflammation and the role of organized colonic patch lymphoid tissues in IBD.
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