Beneficial effects of blocking the IL-23/Th17 pathway in a humanized preclinical MG model - Archive ouverte HAL Accéder directement au contenu
Poster De Conférence Année : 2019

Beneficial effects of blocking the IL-23/Th17 pathway in a humanized preclinical MG model

Résumé

Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies directed against acetylcholine receptor (AChR +). In MG, the thymus is the effector tissue. It harbors chronic inflammation, defective regulatory T-cells and ectopic germinal centers (eGCs) (Berrih-Aknin 2014). We have demonstrated that crosstalk between Th17 cells and thymic epithelial cells, mediated by IL-23 and IL-17, may sustain the thymic pathogenic events supporting the production of autoantibodies by B-cells found in the eGCs (Villegas, Bayer et al. 2019). Objective We evaluate the impact of blocking the IL-23/Th17 axis, on the thymus inflammatory state and MG clinical course in a MG preclinical mouse model. Methods The preclinical MG mouse model consists in engrafting AChR + MG thymic biopsies in immunedeficient NSG mice (NSG-MG) (Sudres, Maurer et al. 2017). NSG-MG mice were treated 25 days after engraftment with a monoclonal antibody anti human IL-23p19. We assessed the effects on thymus and muscle homeostasis and on the MG global clinical score. Results The release of inflammatory T-cells (CD4 + CCR6 + CCR4 + T-cells) and of IL-17 by the engrafted thymus in NSG-MG blood is limited or stopped by the anti IL-23p19 antibody. In addition, a decreased thymic expression of protein involved in eGC stabilization was observed in the engrafted thymus. More, in the muscle tissue, gene expression of muscle satellite cell activation, Pax7 and MyoD is reduced while MyoG, marker of muscle regeneration, is increased by the treatment. Finally, improvements are observed for clinical symptoms and the global disease score. Conclusion Altogether these data suggest that an anti-IL-23 therapy could be beneficial in MG by acting both on the thymus and the muscle. The inhibition of IL-23 : 1) controls the inflammatory state in AChR + MG thymuses, limiting the thymic production autoantibodies; 2) Activates transduction pathways involved in muscle regeneration process and disease amelioration.
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Dates et versions

hal-03843606 , version 1 (13-12-2022)

Identifiants

  • HAL Id : hal-03843606 , version 1

Citer

Jose Adolfo Villegas, Jerôme van Wassenhove, Judith Merrheim, Karen Matta, Frédérique Truffault, et al.. Beneficial effects of blocking the IL-23/Th17 pathway in a humanized preclinical MG model. sfi 2019, Nov 2019, Nantes, France. ⟨hal-03843606⟩
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