SUMMARYOral administration of DSS has been reported to induce an acute and chronic colitis in mice. The aim of our study was to evaluate if the chronic phase of DSS-induced colitis was characterized by a Th1/Th2 response and how this would relate to mucosal regeneration. Swiss Webster mice were fed 5% DSS in their drinking water for 7 days, followed by 2-5 weeks consumption of water. Control mice received only water. The animals were killed at 3 and 6 weeks after induction. Their colons were isolated for histology and immunohistochemistry, using specific MoAbs for T and B cells, macrophages, interferon-gamma (IFNg), IL-4 and IL-5. Colons were scored for inflammation, damage and regeneration. Two weeks after stopping DSS the colonic epithelium had only partially healed. Total colitis scores were still increased, especially in the distal colon, which was due to more inflammation, damage and less regeneration. In areas of incomplete colonic healing the basal parts of the lamina propria contained macrophages and CD4 þ T cells. These CD4 þ T cells showed a focal increase of IFN-g and IL-4 staining compared with control animals. These findings were still observed 5 weeks after stopping DSS in some mice, albeit less extensive. Chronic DSS-induced colitis is characterized by focal epithelial regeneration and a Th1 as well as Th2 cytokine profile. We postulate that chronic immune activation mediated by both populations of Th cells can interfere with colonic healing and can play a role in the pathogenesis of chronic colitis.

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SUMMARYBackground SPD476 (MMX TM mesalazine), is a novel, once daily, high-strength mesalazine formulation (1.2 g/tablet) that utilizes Multi Matrix System TM (MMX) technology to delay and extend delivery of the active drug throughout the colon.

SUMMARYThe influx of monocytes and neutrophils into the inflamed tissue could be an important aspect in the pathogenesis of inflammatory bowel disease (IBD). A membrane protein involved in the monocyte/neutrophil adherence to endothelium is CDllb/CDI8 or aM,82 (complement receptor type 3 = CR3). In the present study the role of CDII b/CDI8 in experimental IBD was studied by treatment with ED7 and OX42, two MoAbs against CDllb/CDI8. Colitis was induced in rats by a single, rectal administration of 30mg 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol 30%. Two hours before and 3 days after induction of colitis, the animals were given an i.v. dose of O'5 mg of either ED7 or OX42 in I ml PBS. Controls received PBS or an irrelevant MoAb. Four days after the last treatment with the antibodies, the rats were killed, and macroscopic damage scores of the colon were determined. Macrophages and granulocytes were studied by immunohistochemistry and quantified by Interaktives Bild Analysen System (IBAS), and myeloperoxidase (MPO) activity in colonic tissue was measured. After treatment with ED7 and OX42 the mean damage score of the colon was reduced from 4·2 in IBD animals to 1·0 and 1,3, respectively. Smaller areas of ulcerations and a decrease in the number of ulcerations were observed compared with PBS-treated rats. Furthermore, the amount of infiltrating monocytes and leucocytes in the submucosa was enormously reduced, as well as MPO activity in the colonic tissue. These results show that treatment with MoAbs against CDllb/CDI8 reduces clinical signs of experimental IBD in rats by a partial blockade of infiltrating macrophages and granulocytes.

SUMMARYOne of the major advances in the understanding of inflammatory bowel disease has been the observation that mice with immunoregulatory defects, such as interleukin-2 knockout ( IL-2 -/-) mice, develop spontaneous gut inflammation. Here we have characterized the immune response in the ileum, caecum and colon of these mice before and after the onset of colitis by examining the cellular infiltrate, the cytokines produced by these cells and the mucosal vascular addressin MAdCAM-1. IL-2 -/-mice developed colitis after 35 days of age and before this the mice were apparently healthy. IL-2 -/-mice aged over 35 days with colitis had large numbers of CD4+, CD8+, ab T-cell receptor (TCR)+ and cd TCR+ T cells, macrophages, dendritic cells and MAdCAM-1+ endothelial cells in the caecum and colon. This was associated with an increase in the number of interferon-c (IFN-c), IL-1 and tumour necrosis factor-a ( TNF-a) transcripts and a decrease in IL-4 and IL-10 transcripts. Treatment of IL-2 -/-mice with cyclosporin A significantly delayed mortality. Interestingly, IL-2 -/-mice under 35 days, although healthy, did show some subtle immunological signs of preclinical disease. There was a significant increase in the number of macrophages and dendritic cells in the colonic lamina propria and increased mRNA for IL-1 and TNF-a. There were also increased numbers of MAdCAM-1+ endothelial cells, but IFN-c transcripts were not elevated. These results suggest that T-cell-mediated colitis in IL-2 -/-mice may be secondary to an initial non-specific inflammation.