Background and Aims

Autoimmune myasthenia gravis (MG) is caused by autoantibodies directed against the acetylcholine receptor (AChR). In MG, the thymus is the effector tissue characterized by a chronic inflammation, defective regulatory T-cells and ectopic germinal centers (eGCs) (Berrih-Aknin 2014). A crosstalk between Th17 cells and thymic epithelial cells, mediated by IL-23 and IL-17, sustains thymic events supporting antibody production by B-cells found in eGCs (Villegas et al. 2019).

We analyzed the effect of blocking the IL-23/Th17 axis, on the thymus and MG clinical course in a MG preclinical mouse model.

Methods

Immune-deficient NSG mice were engrafted with AChR⁺ MG thymic biopsies (NSG-MG). The NSG-MG model recapitulates MG symptoms and development (Sudres et al. 2017). Twenty five days after engraftment, mice were treated with a monoclonal anti human IL-23 antibody. We assessed the treatment effects on the engrafted thymic biopsies, muscle homeostasis and on MG global clinical score.

Results

The treatment limited or stopped the activation of inflammatory T-cells (CD4⁺CCR6⁺ CCR4⁺ T-cells) in the thymus and the periphery. In addition, a decreased thymic expression of protein involved in eGC stabilization was observed. More, increased muscle regeneration gene expression and significant muscular improvements were observed and correlated with amelioration of clinical symptoms and global disease score.

Conclusions

Altogether these data suggest that an anti-IL-23 therapy could be beneficial in MG by acting on the thymic inflammatory state and on muscle physiology. The inhibition of IL-23 activates transduction pathways involved in antibody production and in muscle regeneration process favoring then disease amelioration.