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Title: The role of membrane Tumour Necrosis Factor Alpha in the function and efficacy of anti-tumour necrosis factor antibodies in inflammatory bowel disease
Author: Bell, Iona Maree
ISNI:       0000 0004 7971 7994
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2018
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Tumour Necrosis Factor Alpha (TNFα) is central to the immunopathogenesis of inflammatory bowel disease. It is initially expressed on the cell surface as a trimer, membrane TNFα, and cleaved from the cell surface by TNFα Converting Enzyme (TACE) to release a soluble trimeric form of the cytokine (sTNFα). Infliximab, an anti-TNFα antibody revolutionised the treatment of IBD. However infliximab is ineffective in up to a third and nearly half of patients lose response to infliximab over time. As yet the mechanisms of action of infliximab are unclear, although the importance of mTNFα is emerging. The aim of the study was to establish whether pharmacological and endogenous TACE inhibitors change the expression of mTNFα with a reciprocal change in sTNFα and other pro-inflammatory cytokines. Additionally possible mechanisms of action of anti-TNFα antibodies were tested. The expression of mTNFα and sTNFα were measured with FACS and ELISA respectively in vitro and ex vivo in controls and IBD patients. The functional effects of infliximab and etanercept were explored using a TNFα transfected CHO cell line and peripheral blood and lamina propria mononuclear cells. Changes in receptor tyrosine kinase (RTK) phosphorylation as a result of TNFα neutralisation in IBD explants were determined using a RTK phosphoarray. A significant reduction in sTNFα and an increase in mTNFα were seen with some TACE inhibitors, without any change in other pro-inflammatory cytokines. Apoptosis was not seen with anti-TNFα antibodies in either the TNFα expressing cell line or in PBMCs. The study showed for the first time that infliximab reduces phosphorylation of RTKs such as EGFR, FGFR, Eph as well as those involved in T cell receptor signalling such as ZAP-70 and Lck.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Inflammatory Bowel Disease ; Tumour Necrosis Factor Alpha