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- W2920682973 abstract "Career situation of first and presenting author Post-doctoral fellow. Introduction Anti-TNF agents are widely used in rheumatoid arthritis (RA). Their effect on inflammation results from the neutralization of soluble TNF (sTNF), but also supposedly from the induction of reverse signaling through their binding to membrane TNF (tmTNF). Despite possible clinical relevance, reverse signaling has been described only in vitro but has not been proven in vivo. Objectives In this study we aim to demonstrate for the first time the existence of tmTNF reverse signaling in vivo and its importance in anti-TNF response during arthritis. Methods Triple transgenic mouse model (3TG), KO for TNFR1/TNFR2 and KI for tmTNF, thus secreting no sTNF was developed. To analyze reverse signaling, mice were injected either with etanercept (ETA, 10 mg/kg), an anti-mouse TNF antibody (MP6-XT22, rat IgG1, 10 mg/kg) or an anti-human IL17 antibody (secukinumab, SEC, 10 mg/kg) as a control. Daily clinical evaluation of K/BxN serum induced-arthritis was performed in 3TG as well as WT mice. Polarization of bone marrow-derived macrophages (BMDM) and cytokine production from non-arthritic WT and 3TG mice under the action of anti-TNF in vitro was evaluated by RT-qPCR, CBA and ELISA. Results In vivo, the administration of anti-TNF (ETA or MP6-XT22) decreased arthritic scores in WT mice (p=0.005) as well as in 3TG mice (p Conclusions Our work provides in vivo evidence for the involvement of reverse signaling in the anti-TNF-mediated modulation of arthritis. Reverse signaling is expected to result in the modulation of macrophage polarization from an inflammatory to an alternative functional phenotype in arthritic mice. Our data prompt us to consider new interpretation of the effects of anti-TNF in the treatment of RA. Disclosure of Interest None declared." @default.
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- W2920682973 date "2019-03-01" @default.
- W2920682973 modified "2023-09-22" @default.
- W2920682973 title "P038 In vivo demonstration of tmTNF reverse signaling: significance in the therapeutic response to anti-TNF agents during murine arthritis" @default.
- W2920682973 doi "https://doi.org/10.1136/annrheumdis-2018-ewrr2019.30" @default.
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