Robert P. McCabe

The goal of this section is to define the optimal method(s) of detecting colon dysplasia in patients with IBD. Detection of dysplasia, which is the immediate goal of surveillance colonoscopy, was chosen as the primary endpoint, with the understanding that detection of dysplasia is not clearly documented to improve clinical outcomes such as CRC incidence or mortality. Only histologic diagnoses of lowgrade or high-grade dysplasia were considered; diagnoses of indefinite for dysplasia were excluded. Current guideline recommendations regarding the need for serial surveillance colonoscopy in patients with IBD were accepted, and other issues such as the appropriate surveillance interval or risk stratification 1-4,8-10 were not addressed.

C3H/HeJBir mice are a new substrain that spontaneously develop colitis early in life. This study was done to determine the T cell reactivity of C3H/HeJBir mice to candidate antigens that might be involved in their disease. C3H/HeJBir CD4+ T cells were strongly reactive to antigens of the enteric bacterial flora, but not to epithelial or food antigens. The stimulatory material in the enteric bacteria was trypsin sensitive and restricted by class II major histocompatibility complex molecules, but did not have the properties of a superantigen. The precursor frequency of interleuken (IL)-2-producing, bacterial-reactive CD4+ T cells in colitic mice was 1 out of 2,000 compared to 1 out of 20,000-25,000 in noncolitic control mice. These T cells produced predominately IL-2 and interferon gamma, consistent with a T helper type 1 cell response and were present at 3-4 wk, the age of onset of the colitis. Adoptive transfer of bacterial-antigen-activated CD4+ T cells from colitic C3H/HeJBir but not from control C3H/HeJ mice into C3H/HeSnJ scid/scid recipients induced colitis. These data represent a direct demonstration that T cells reactive with conventional antigens of the enteric bacterial flora can mediate chronic inflammatory bowel disease.

The idiopathic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are chronic disorders that appear to arise from an aberrant interaction of environmental, genetic, and immunologic factors. The aim of this study was to examine the immune reactivity of a spontaneously colitic mouse strain, C3H/HeJBir, to epithelial, food, and enteric bacterial Ags. Serum Ab responses of colitic C3H/HeJBir and noncolitic parental C3H/HeJ mice were measured by enhanced chemiluminescence Western blotting. No reactivity to epithelial or food Ags was detected. However, the sera from C3H/HeJBir mice had a reproducible banding pattern on Western blot to bacterial Ags, whereas sera from C3H/HeJ mice did not. Only a small, highly selected number of enteric bacterial Ags were recognized. There were major differences in the degree of recognition of different bacterial strains, marked by remarkably few Abs to Ags of the major anaerobes of the bacterial flora. The serum Abs detected on immunoblot were primarily IgG2a, suggesting a Th1 response. Comparison of sera reactivity to histopathologic severity showed an inverse relationship: one third of young C3H/HeJBir mice during the peak of colitis produced Abs to bacterial Ags, while later in life, when the colitis had resolved, 96% produced Abs. These data are consistent with an abnormal immune reactivity to enteric bacterial flora in C3H/HeJBir mice, a reactivity that is highly selective considering the abundant bacterial Ags present in the colon lumen. We postulate that this reactivity plays a role in the pathogenesis of colitis in these mice.

Experimental animal models, particularly the newer mouse models, have convincingly demonstrated that CD+ T cells play a central role in chronic intestinal inflammation. Such CD4+ effector T cells are induced by the bacterial flora. In at least one model, it is conventional protein antigens that are stimulating these pathogenic T cells. The antigens driving disease seem to be a selective subset of immunodominant proteins, likely derived from a subset of organisms. Multiple genes contribute to colitis susceptibility and a number of these genes are being localized.