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Title: Regulatory T cells in rheumatoid arthritis : the role of TNF-α receptor signaling and DNA methylation
Author: Tseng, Wen-Yi
ISNI:       0000 0004 7653 3153
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Anti-TNF-α therapy has revolutionised the management of inflammatory arthritis, leading to improvement of symptoms and signs of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, as well as inhibiting radiographic progression in rheumatoid arthritis, and psoriatic arthritis. However, despite its success in the majority of patients with inflammatory arthritis, about 20-40% of patients are resistant to anti-TNF-α treatment and few patients (10% or less) achieve long-term remission. Several studies suggest that TNF-α receptor 2 (TNFR2) plays an immunoregulatory role in arthritis and that the interruption of TNF/TNFR2 interaction contributes to resistance to anti-TNF-α therapy and to some of the adverse effects associated with anti-TNF-α therapy. The objective of the work presented in this thesis was to gain a deeper understanding of TNFR signalling in rheumatoid arthritis with particular emphasis on a sub-population of lymphocytes known as regulatory T cells (Tregs). Firstly, an association was shown between TNFR2 signaling and TGF-β in regulating the expression of the Treg associated transcription factor, FoxP3. I further assessed the effect of TNFR signaling on CpG methylation at the FoxP3 locus by bisulfite sequencing. The result showed that TNFR2 deficiency leads to increased level of DNA methylation in the proximal promoter of FoxP3. Secondly, I investigated the role of TNFR signaling in arthritis. As expected, TNFR1-/- mice were found to be relatively resistant to arthritis. In contrast to TNFR1-/- mice, higher incidence and increased disease activity were observed in TNFR2-/- mice compared to wild-type mice. In addition, the results showed that TNFR2 deficiency leads to decreased numbers of Tregs, reduced FoxP3 expression of Tregs, reduced expression of immune inhibitory markers and increased production of pro-inflammatory cytokines in arthritis. Thirdly, I investigated the therapeutic potential of DNA demethylating agents in the treatment of RA. It showed that the DNA demethylating drug, decitabine, ameliorated collagen-induced arthritis (an animal model of rheumatoid arthritis) and promoted Treg suppressive function whilst inhibiting pathogenic Th1/Th17 cells. These findings highlight the therapeutic potential of strategies to boost Tregs by TNFR2 agonists or DNA demethylating agents and suggest that it may be possible to achieve long term inhibition of pathogenic inflammation using this approach.
Supervisor: Williams, Richard Owen ; Feldmann, Marc Sponsor: Chang Gung Memorial Hospital ; Ministry of Education Republic of China (Taiwan)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available