title: Tyrosine kinase inhibitors ameliorate autoimmune encephalomyelitis in a mouse model of multiple sclerosis.
abstract: Multiple sclerosis is an autoimmune disease of the central nervous system characterized by neuroinflammation and demyelination. Although considered a T cell-mediated disease, multiple sclerosis involves the activation of both adaptive and innate immune cells, as well as resident cells of the central nervous system, which synergize in inducing inflammation and thereby demyelination. Differentiation, survival, and inflammatory functions of innate immune cells and of astrocytes of the central nervous system are regulated by tyrosine kinases. Here, we show that imatinib, sorafenib, and GW2580-small molecule tyrosine kinase inhibitors-can each prevent the development of disease and treat established disease in a mouse model of multiple sclerosis. In vitro, imatinib and sorafenib inhibited astrocyte proliferation mediated by the tyrosine kinase platelet-derived growth factor receptor (PDGFR), whereas GW2580 and sorafenib inhibited macrophage tumor necrosis factor (TNF) production mediated by the tyrosine kinases c-Fms and PDGFR, respectively. In vivo, amelioration of disease by GW2580 was associated with a reduction in the proportion of macrophages and T cells in the CNS infiltrate, as well as a reduction in the levels of circulating TNF. Our findings suggest that GW2580 and the FDA-approved drugs imatinib and sorafenib have potential as novel therapeutics for the treatment of autoimmune demyelinating disease.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Crespo
authors.forename: Stacey C
authors.initials: SC
authors.lastname: Kang
authors.forename: Richard
authors.initials: R
authors.lastname: Daneman
authors.forename: Tamsin M
authors.initials: TM
authors.lastname: Lindstrom
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000009:adverse effects; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001549:Benzamides; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D001549:Benzamides; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D017479:Receptors, Platelet-Derived Growth Factor