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Negative regulation of the JAK/STAT signalling pathway in inflammatory arthritis

Derrac Soria, Alicia 2020. Negative regulation of the JAK/STAT signalling pathway in inflammatory arthritis. PhD Thesis, Cardiff University.
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Abstract

Background ¾ Rheumatoid arthritis (RA) is one of the most common forms of autoimmune disease, affecting about 1% of the population and causing chronic inflammation that primarily affects the joints. Cytokines that signal via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway are major drivers of synovitis in patients with RA and contribute to the rapid progression of the disease. Biological agents targeting the cytokine interleukin (IL)-6, its receptor system or downstream pathway have revolutionised the treatment of immune-mediated diseases and can induce drug-free remission. However, RA is a highly heterogeneous and complex disease and consequently, around 40% of patients do not respond to current frontline biologics. This has raised the need for alternative therapeutic strategies or precision medicine approaches that improve treatment decisions for RA patients. My thesis aimed to investigate the action of novel therapeutic modalities that target the IL-6 receptor system or downstream signalling cassette to improve understanding of the underlying inflammatory processes that drive synovitis. Results ¾ Exploiting three novel classes of IL-6/STAT3 inhibitors, I have interrogated their mode of action in in vitro model systems and animal models of synovitis. (1) Using histopathology and RNA-sequencing of the inflamed synovium, I demonstrated that an anti-cancer therapy (CpG-Stat3siRNA) improved arthritis outcome, altered the balance of STAT1/STAT3 signalling and reduced the incidence of ectopic lymphoid-like structures in synovitis. (2) I also used a virus-derived SOCS3 modulator peptide that suppresses STAT3 activity through the induction of SOCS3. This agent was shown to block pathogenic Thelper (Th)17 cell differentiation in vitro and reduced disease pathology in mice with antigen-induced arthritis. (3) Blocking of IL-6 trans-signalling pathway with engineered inhibitors (cs-130Fc) based on regulatory domains of the sgp130 receptor proved efficacy over other related therapy variants (e.g., olamkicept) in inhibiting STAT3-driven Th17 cell expansion in vitro. In a final approach, I also examined the biology of genes that are suppressed by IL-6 and IL-27 in CD4+ T-cells. These factors might have immune-protective function in synovitis, and initial studies are presented on the identification of CRTAM as one such factor and its inflammatory regulation in mouse synovitis. Conclusions ¾ These studies showcase how JAK/STAT signalling through the IL-6 receptor cassette may be controlled at multiple levels and further demonstrate how investigations into their mode of action help to unearth new understanding of IL-6 biology in RA.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Funders: Versus Arthritis, Wellcome Trust
Date of First Compliant Deposit: 4 December 2020
Last Modified: 04 Dec 2020 11:58
URI: http://orca-mwe.cf.ac.uk/id/eprint/136775

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