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Title: Mechanisms of immune activation and regulation in chronic inflammatory diseases of the gut
Author: Ricciardelli, I.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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The gastrointestinal (GI) tract is the largest surface area of the body exposed to the external environment and it is subject to constant challenge from micro-organisms and food-derived antigens. Stringent regulation of the immune system of the gut is vital, as breakdown in tolerance to commensal bacteria in Inflammatory Bowel Diseases (IBD, such as Crohn's disease and Ulcerative Colitis (UC)) or to dietary antigens such as gluten in Celiac disease (CD) can lead to inflammation. Hence induction and maintenance of mucosal tolerance is of paramount importance to avoid inappropriate immune responses within the intestine. The aim of this thesis was to investigate the mechanisms of activation and regulation in these intestinal autoimmune diseases. Firstly, I have investigated the mechanisms of immune regulation of mucosal tolerance looking at the role of regulatory T cells such as CD4+CD25+FOXP3+ T cells in IBD and CD. Here I show that anti TNF-oc treatment in vivo with Infliximab in Crohn's patients does not solely neutralise TNF-a, but also affects activation and possibly expansion of mucosal regulatory T cells. I suggest that anti TNF-a immunotherapy can also restore mucosal homeostasis in Crohn's disease. Furthermore, I show that anti IL-2 Receptor (CD25) treatment in vivo in UC down-regulates the frequency of mucosal regulatory T cells with an improvement of the disease. In CD I observed that antigenic challenge in vitro with gluten up-regulates regulatory T cells but despite this, mucosal homeostasis is not restored. My observations show how complex is the homeostatic balance of regulatory T cells response in different GI pathologies. Next I have investigated the mechanisms of activation of the innate immune response that induce modifications like actin reorganization, protein tyrosine phosphorylation and apoptosis of the epithelial cells in CD. I have therefore explored which signalling pathway on epithelial cells might be involved in these early responses involving the innate immune system. The role of the small GTPase Rho-A pathway has been investigated as possible candidate in modulating these modifications. Here I demonstrate the role of Rho-A GTPase pathway in the innate immune response to gluten with epithelial cell modifications in CD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available