CHARACTERIZATION OF THE MUCOSAL CELL-MEDIATED IMMUNE-RESPONSE IN IL-2KNOCKOUT MICE BEFORE AND AFTER THE ONSET OF COLITIS

One of the major advances in the understanding of inflammatory bowel d isease has been the observation that mice with immunoregulatory defect s, such as interleukin-2 knockout (IL-2 -/-) mice, develop spontaneous gut inflammation. Here we have characterized the immune response in t he 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 -/- m ice developed colitis after 35 days of age and before this the mice we re apparently healthy. IL-2 -/- mice aged over 35 days with colitis ha d large numbers of CD4(+), CD8(+), alpha beta T-cell receptor (TCR)(+) and gamma delta TCR+ T cells, macrophages, dendritic cells and MAdCAM -1(+) endothelial cells in the caecum and colon. This was associated w ith an increase in the number of interferon-gamma (IFN-gamma), IL-1 an d tumour necrosis factor-alpha (TNF-alpha) transcripts and a decrease in IL-4 and IL-10 transcripts. Treatment of IL-2 -/- mice with cyclosp orin A significantly delayed mortality. Interestingly, IL-2 -/- mice u nder 35 days, although healthy, did show some subtle immunological sig ns of preclinical disease. There was a significant increase in the num ber of macrophages and dendritic cells in the colonic lamina propria a nd increased mRNA for IL-1 and TNF-alpha. There were also increased nu mbers of MAdCAM-1(+) endothelial cells, but IFN-gamma transcripts were not elevated. These results suggest that T-cell-mediated colitis in I L-2 -/- mice may be secondary to an initial non-specific inflammation.