Targeting the GM-CSF receptor for the treatment of CNS autoimmunity. (November 2017)

• Record Type: Journal Article
• Authors: Ifergan, Igal; Davidson, Todd S.; Kebir, Hania; Xu, Dan; Palacios-Macapagal, Daphne; Cann, Jennifer; Rodgers, Jane M.; Hunter, Zoe N.; Pittet, Camille L.; Beddow, Sara; Jones, Clare A.; Prat, Alexandre; Sleeman, Matthew A.; Miller, Stephen D.
• Is Part Of: Journal of autoimmunity. Volume 84(2017)
• Page Start: 1
• Page End: 11
• Publication Date: 2017-11
• Subjects: GM-CSF -- Multiple sclerosis -- MS -- EAE -- Dendritic cells -- Inflammatory monocytes; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.06.005
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα + myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS. Highlights: Targeting the GM-CSF receptor prevents and treats different animal models of MS. GM-CSF blockade reduces T cell responses to the inducing and relapsing peptides. Anti-GM-CSF Rα treatment reduces mDCs and inflammatory monocytes activation. Anti-GM-CSF Rα reduces chemokine receptor expression.