Regulation Of Immune Responses In Humans And Non-human P

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Abstract

In previous studies we have shown that intra-rectal administration of oxazalone in an ethanol vehicle results in the rapid development of colitis characterized by ulceration, the influx of acute and chronic inflammatory cells in the superficial layer of the gut and bowel wall edema. This histologic picture was more like ulcerative colitis (UC) than Crohn?s disease (CD) and differed from the colitis induced by TNBS which resembles CD. Indeed, the cytokine profiles of the two colitides also differed: oxazalone colitis was a Th2 colitis marked by high level production of IL-4 and IL-5 whereas TNBS colitis was a Th1 colitis associated with high level production of IL-12 and IFN-g. These profiles were consistent with the cytokine patterns in the counterpart human diseases; thus, while UC is not associated with high IL-4 levels it is associated with high IL-5 levels and, in contrast, CD is associated with high IL-12 and IFN-g levels. In a new study of oxazalone colitis, we first developed a more longer lasting inflammation by pre-sensitizing the mice by skin painting and administering lower intra-rectal doses of contactant; this allowed a more detailed study of disease progression. Using this approach we showed that the initial increase in IL-4 production is rapidly superceded by a robust IL-13 response. Moreover, this IL-13 was shown to be an essential pathologic feature of the colitis as the latter could be prevented by administration of an IL-13 inhibitor (IL-13Ra2-Fc). In further studies we showed that the development of oxazalone colitis depends on the presence of an NK1.1+ cell since pre-treatment of mice with a monoclonal antibody also prevented disease development. We then determined that the effector cell was in fact a NK-T cell since: 1) disease was prevented by administration of anti-CD1 antibody; 2) disease could not be induced in b2m-deficient mice, CD1-deficient mice and Ja281 deficient mice, i.e., mice molecular machinery for NK-T cell responses. In a final series of studies, the research team showed that it was in fact the NK-T cells that were producing the IL-13. This was shown by the fact that stimulation of cells from mice with colitis with a glycolipid antigen (agalacosylceramide) that is only presented to T cells in the context of CD1 and only stimulates NK-T cells elicits a high IL-13 response. These results show for the first time that colitis can be mediated by NK-T cells producing a Th2 cytokine, IL-13. Their significance lies in the fact that ulcerative colitis may be caused by similar immunologic mechanisms.