Dogan, Ahmet; (1995) Expression and regulation of cell adhesion molecules in human intestine. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this thesis, the expression and regulation of cell adhesion molecules (CAM) in the intestinal microenvironment during the development of human fetal intestine, in inflammatory bowel disease and in a fetal gut organ culture model in which a T cell mediated enteropathy can be generated are described. When immunohistochemistry was used to study CAM expression in normal human fetal intestine, the distribution of ICAM-1 and VCAM-1 expression suggested these molecules may be involved in the accumulation and organisation of gut associated lymphoid tissue. In fetal gut organ cultures, in which local T cells were stimulated with mitogens, the expression of ICAM-1, VCAM-1 and E-selectin was increased compared to control cultures, whereas the expression of P-selectin and PECAM-1 was not. Immunosuppressive agents cyclosporin A, FK506 and dexamethasone prevented the increase in CAM expression in most cases. However addition of cyclosporin A to mitogen stimulated fetal gut organ cultures increased and prolonged E-selectin expression. This unexpected finding was only seen with cyclosporin A but not with other immuno-suppressants. Experiments with isolated endothelial cells suggested it was not a direct effect of cyclosporine A on endothelial cells, but was a consequence of cells or cellular products acting in the mucosal micro-environment. Endothelial CAM expression in Crohn's disease, before and after treatment with enteral nutrition or cyclosporin A was investigated. Despite significant clinical and histological improvement after treatment, no change in the level of CAM expression was noted suggesting that low level chronic inflammation continues in clinical remission. The expression of homotypic epithelial cell adhesion molecule, E-cadherin was studied in normal and inflamed intestine. The most significant finding was comparatively lower expression of E-cadherin by the ulcer associated cell lineage in Crohn's disease, in line with reparative function and higher mobility of this lineage. Finally, monoclonal antibodies were raised against mitogen stimulated fetal gut in search of novel antigens induced in intestinal inflammation. Several clones were produced which were reactive with an antigen expressed by neutrophils and epithelial cells. Epithelial expression of this antigen was upregulated in intestinal inflammation. The antibodies were shown to recognize members of the carcinoembryonic antigen (CEA) protein family. CEA proteins act as adhesion molecules and the increased expression may result in increased epithelial stability in inflammation.

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