TH17/IL-23 TARGETED THERAPY IN A HUMANIZED MOUSE MODEL OF MYASTHENIA GRAVIS - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2018

TH17/IL-23 TARGETED THERAPY IN A HUMANIZED MOUSE MODEL OF MYASTHENIA GRAVIS

Résumé

Background Autoimmune Myasthenia Gravis (MG) is a neuromuscular disease mainly caused by auto-antibodies against the acetylcholine receptor (AChR+). AChR+-MG young patients display hyperplastic thymus with ectopic germinal centers. In addition, MG thymuses exhibit a chronic inflammatory state illustrated by dysfunctional regulatory T cells (Treg) while the pro-inflammatory T-cells (i.e. Th17 cells, CD4+CCR6+IL23R+) are over-activated (Gradolatto et.al., 2014). We recently developed a humanized preclinical MG model into immune-deficient NSG mice (NSG-MG), and we could demonstrate that grafting thymic MG fragments could lead to the development of myasthenic symptoms (Sudres et.al., 2017), making this model relevant for testing new therapies Method The aim of the study was to evaluate the impact of blocking IL-23, a critical cytokine involved in Th17 cell differentiation, thymus inflammatory state and MG clinical course in the NSG-MG model. Results Our data show that engrafted human AChR+ MG thymuses release a higher percentage of inflammatory T cells (CD4+CCR6+) and IgG in NSG-MG blood than control thymuses. Treatment of NSG-MG mice with a monoclonal anti-human IL-23p19 antibody decreased circulating IgGs, and CD4+CCR6+ inflammatory T-cells. More, RT-PCR analyses of engrafted human MG thymuses, after six weeks, showed a reduced expression of IL-17 in mice receiving the monoclonal antibody, although no improvement in the clinical symptoms (muscle force) was observed Conclusion Altogether these data suggest that anti-IL-23p19 decreases 1) the inflammatory state in AChR+ MG thymuses by controlling Th17 cell differentiation 2) thymic IgG production. However, these changes appear insufficient to limit AChR antibody effects in the periphery and therefore to control the clinical symptoms
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Dates et versions

hal-03843470 , version 1 (16-11-2022)

Identifiants

  • HAL Id : hal-03843470 , version 1

Citer

Jose Adolfo Villegas, Jérôme van Wassenhove, Alexandra Clarissa Bayer Wildberger, Régine Roussin, Nicola Santelmo, et al.. TH17/IL-23 TARGETED THERAPY IN A HUMANIZED MOUSE MODEL OF MYASTHENIA GRAVIS. Autoimmunity 2018, May 2018, Lisbone, Portugal. ⟨hal-03843470⟩
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