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IL-6 SIL-6r in rheumatoid arthritis: Interplay with TNFa and implications in anti-TNFa therapy

Carty, Sara Madelaine 2008. IL-6 SIL-6r in rheumatoid arthritis: Interplay with TNFa and implications in anti-TNFa therapy. PhD Thesis, Cardiff University.

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Abstract

Recent advances in the therapeutic management of rheumatoid arthritis have identified that selective targeting of inflammatory cytokines represents a valid approach to the treatment of rheumatoid arthritis (RA). Although blockade of the inflammatory response at its inception by anti-TNFalpha agents has shown considerable clinical promise, this approach is not without its drawbacks. Consequently, identification of novel therapeutic strategies is essential. In recent clinical trials, favourable results were found with modalities that block interleukin-6 signalling. However, it is unclear whether blockade of IL-6 bioactivity offers a true advantage over anti-TNFalpha therapies, and raises the possibility of combination therapies for selected patient cohorts. The ultimate objective of this thesis was to provide proof of concept that combination TNFalpha and IL-6 blockade may offer true advantages in selected RA patient cohorts. To elicit a response from a target cell, IL-6 must first form a complex with its receptor. It was found that neutrophils and macrophages within the RA joint had lower levels of IL-6R expression than neutrophils and macrophages obtained from matched blood samples in the same patients. Stimulation of neutrophils with TNFalpha led to rapid shedding of cell surface IL-6R. TNFa and IL-6 trans-signalling interacted to modulate chemokine production (particularly CCL2 macrophage chemo-attractant) and adhesion molecule expression (ICAM-1) on RA synovial fibroblasts. This could lead to significant effects on leucocyte recruitment in the RA joint. A murine model of arthritis (collagen induced arthritis) was used to investigate the efficacy of combination therapy with sgp130:Fc and etanercept on clinical and pathological outcomes of disease. Combination therapy for rnCIA resulted in reduction in clinical disease severity. Macrophage recruitment was reduced and all parameters of histological damage. It appears that there is now proof of concept for the theory that combination therapy with etanercept and sgp130:FC may be effective in selected patients with rheumatoid arthritis.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
ISBN: 9781303185427
Funders: Wellcome Trust, Cardiff University
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Jun 2019 02:22
URI: http://orca-mwe.cf.ac.uk/id/eprint/55795

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