Microbiology & Immunology - Theses

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Author: Brown, Steven J × End date: 2009 × Start date: 2000 ×

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    Immunological studies of a glycosylation-based mouse model of colitis
    Brown, Steven J ( 2004-04)
    Immune dysfunction is a well-recognized factor in the pathogenesis of Inflammatory Bowel Disease (IBD). Numerous mouse models of colitis highlight how varied immunological defects, particularly of T-cells, can give rise to intestinal inflammation. It is increasingly recognized that glycosylation status has a major impact on the development and function of T-cells. In particular maturation in the thymus is regulated by a number of glycosylation-dependent mechanisms. Abnormal glycosylation has been identified in human IBD although this is almost entirely within the context of the mucosal barrier. Mice transgenic for a human glycosyltransferase (α1-2fucosyltransferase, hFUT1) were generated at our institution. These mice were subsequently observed to develop colitis and thus they provide an opportunity to examine the relative importance of glycosylation-induced defects in barrier function or immune function in the pathogenesis of colitis. The aim of this thesis was to further characterize this model, with a particular emphasis on identifying the pathological mechanism behind the intestinal inflammation. It was observed that hFUT1 mice have a profound and unexpected defect in T-cell development. A marked peripheral T-cell deficiency was evident, including a near total absence of CD4 CD25 regulatory T-cells. Examination of the thymus revealed a complete maturation block at the cortico-medullary transition point with profound disturbances in thymocyte glycosylation patterns. The glycosylation defects present were shown to be directly due to the transgene and to inhibit the normal glycosylation changes that mediate thymocyte maturation. Full immune reconstitution experiments confirmed that the abnormal thymocyte glycosylation is responsible for the maturation arrest, the peripheral T-cell deficiency and the observed colitis. A number of therapeutic studies were also undertaken, with prevention of colitis also observed with IL-12 blockade and with manipulation of the intestinal microflora.