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Title: Molecular targeting in inflammatory bowel disease : an investigation to identify novel chemokine targets for the potential development of new therapeutic agents for inflammatory bowel disease
Author: Puleston, Joanne Mary
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2005
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Purpose Inflammatory bowel disease is characterised by intense mucosal recruitment of activated leukocytes. As chemokines determine inflammatory leukocyte recruitment and retention, the expression of the entire chemokine family within colonic mucosa from IBD patients was compared to non-inflamed and inflamed controls. Methods A microarray of cDNAs, representing the entire chemokine superfamily and their cognate receptors, was hybridised with probes derived from colonoscopic biopsies. While expression levels of individual chemokines and their receptors have been measured in colon tissue previously, no one has attempted to analyse transcription levels of the entire chemokine superfamily in parallel The array levels were correlated with histopathological inflammatory scores and expression of their cognate receptors by quantitative PCR and immunohistochemistry. Flow cytometry was performed on mucosally-derived colonic cells. Caco-2, HT29, T84, primary colonic epithelium and keratinocyte cell lines were stimulated with combinations of IL-1f , TNF-u, and LPS, and analysed using the same microarray. Results Expression of a distinct subset of chemokines, consisting of CXCL's 1-3 and 8 and CCL20, was up regulated in active colonic IBD, compared to non-inflamed areas or tissue from controls. This expression pattern correlated with histopathological inflammatory scores Increased expression of their cognate receptors, CXCR1, CXCR2 and CCR6, was confirmed by quantitative PCR and immunohistochemistry. Flow cytometric revealed an increase of CCL20 expression on epithelial cells in IBD specimens, particularly in severe disease. An identical chemokine response was induced in Caco-2 cells by stimulation with IL-1p, but not TNF-a By contrast, IL-1p and TNF-a were synergistic in HT29 and keratinocytes. Conclusion IL-1fi and TNF-a appear to be the pivotal mediators of a coordinated epithelial chemokine response that dominates the mucosal environment in ulcerative colitis. These data suggest several new therapeutic targets for IBD, as well as identifying a previously unrecognised coordinated epithelial chemokine response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available