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Targeting the IL-23/Th17 pathway to treat Myasthenia Gravis

Abstract : Myasthenia gravis (MG) is an autoimmune neuromuscular disease caused by autoantibodies to acetylcholine receptors. The MG thymus is inflammatory and harbors germinal centers, site for the production of autoantibodies and an overexpression of cytokines favoring the development of Th17 cells. Associated with this cytokine cocktail, IL-23 promotes the emergence of deleterious Th17 cells. The objectives of my thesis were to 1) Determine the roles of the IL-23 / Th17 pathway in pathogenic thymic events. 2) to identify, in vivo, the beneficial effects of an IL-23 targeting therapy on two preclinical mouse models of MG. We observed in MG patients, a thymic over-expression of IL-23, responsible for pathogenic Th17 cells and their increased secretion of IL-17. In addition, Th17 cells function as positive feedback on IL-23, feeding a chronic loop of thymic inflammation. In the NSG-MG humanized mouse model, we show that blockade of IL-23 induces a reduction in the percentage of thymic and circulating Th17cells, as well as a decrease in the thymic expression of structural proteins of germinal centers. In the classical mouse model of MG, EAMG, anti IL-23 therapy induces a decrease in circulating levels of autoantibodies, inflammatory markers and activation of muscle stem cells, concomitant with activation of muscle regeneration markers. In both models, a significant decrease in the clinical signs of MG is observed. In conclusion, IL-23 appears to be a potential therapeutic target for MG.
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https://tel.archives-ouvertes.fr/tel-03139848
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Submitted on : Friday, February 12, 2021 - 12:36:53 PM
Last modification on : Friday, March 19, 2021 - 11:20:01 AM
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  • HAL Id : tel-03139848, version 1

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José Adolfo Villegas Vázquez. Targeting the IL-23/Th17 pathway to treat Myasthenia Gravis. Immunology. Sorbonne Université, 2019. English. ⟨NNT : 2019SORUS393⟩. ⟨tel-03139848⟩

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