THU0051 Tnf receptor 2 plays an immunoregulatory and anti-inflammatory role in arthritis

Abstract

BackgroundDespite the overall success of TNFα inhibitors in rheumatoid arthritis (RA), up to half of patients are classified as either primary or secondary non-responders1. One hypothesis put forward to explain resistance to anti-TNFα therapy is an ascendant effect of dysregulated regulatory T cells and increased Th17 responses following TNFα blockade. Previous studies have demonstrated that TNFR2 is critical for stabilisation and suppressive function of regulatory T cells2,3. However, TNFR2 also activates pro-inflammatory signalling cascades and, to date, the net effect of TNFR2 on the pathogenesis of RA remains unclear.ObjectivesIn this study we address this question by assessing the progression of collagen-induced arthritis (CIA) in mice deficient for TNFR1 or TNFR2.MethodsC57Bl/6N.Q (H-2q) mice were immunised with bovine type II collagen emulsified in complete Freund’s adjuvant. The mice were monitored daily for arthritis and scored clinically from the day of onset of disease. Mice were culled on day 10 after arthritis onset and spleens, lymph nodes, serum and paws were collected for further analysis.ResultsAs expected, TNFR1-/- mice were found to be largely resistant to arthritis both clinically and histologically (figure 1). In contrast, there was significantly enhanced disease activity at the clinical and histological levels in TNFR2-/- mice (figure 1) and this was accompanied by increased expression of the pro-inflammatory cytokines, TNFα and IL-6, reduced numbers of regulatory T cells, reduced FoxP3 expression and reduced expression of the immune inhibitory molecules, PD-1 and LAG3, in TNFR2-/- mice compared to WT mice.Abstract THU0051 – Figure 1Progression of CIA in mice deficient for TNFR1 or TNFR2ConclusionsThis study has shown that TNFR2 signalling plays immunoregulatory and anti-inflammatory roles in CIA. First, it contributes to promotion of regulatory T cell generation and FoxP3 expression, and second, it limits the expression of pro-inflammatory cytokines. TNFR2 also regulates the expression immune inhibitory molecules during inflammation. The results support the rationale to for development of TNFR1 specific antagonists or TNFR2 agonists for the treatment of RA.References[1] Giulia Roda, et al. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clinical and Translational Gastroenterology2016.[2] Xin Chen, et al. TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory enviroment. J. Immunol2013.[3] Xin Chen et al. Expression of TNFR2 defines a maximally suppressive subset of mouse CD4 +CD25+FoxP3+T regulatory cells: applicability to tumour infiltrating T regulatory cells. J. Immunology 2008.AcknowledgementsThis work was supported by grants from Chang Gung Memorial Hospital and Ministry of Science and Technology (Taiwan)Disclosure of InterestNone declared