Targeting the GM-CSF receptor for the treatment of CNS autoimmunity

• Published in: Journal of autoimmunity Vol. 84; pp. 1 - 11
• Main 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2017
• Subjects: Adult; Aged; Aged, 80 and over; Allergy and Immunology; Animals; Antibodies, Monoclonal - therapeutic use; Autoimmunity; Cell Differentiation; Cell Movement; Cells, Cultured; Central Nervous System - immunology; Dendritic cells; Dendritic Cells - immunology; Disease Progression; EAE; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - therapy; Female; GM-CSF; Humans; Immunosuppression; Inflammatory monocytes; Male; Mice; Mice, Inbred C57BL; Middle Aged; Molecular Targeted Therapy; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - therapy; Myelin Sheath - immunology; Myeloid Cells - immunology; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Signal Transduction; T-Lymphocytes - immunology; EAE; Multiple sclerosis; Dendritic cells; GM-CSF; Inflammatory monocytes; MS
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2017.06.005

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.