Journal of Clinical Immunology

, Volume 31, Issue 6, pp 1010–1020

Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis

  • Oliver Crespo
  • Stacey C. Kang
  • Richard Daneman
  • Tamsin M. Lindstrom
  • Peggy P. Ho
  • Raymond A. Sobel
  • Lawrence Steinman
  • William H. Robinson
Article

DOI: 10.1007/s10875-011-9579-6

Cite this article as:
Crespo, O., Kang, S.C., Daneman, R. et al. J Clin Immunol (2011) 31: 1010. doi:10.1007/s10875-011-9579-6

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.

Keywords

Imatinib sorafenib experimental autoimmune encephalomyelitis tyrosine kinase inhibitors macrophages TNF astrocyte proliferation 

Abbreviations

MS

Multiple sclerosis

EAE

Experimental autoimmune encephalomyelitis

MOG

Myelin oligodendrocyte glycoprotein

TKI

Tyrosine kinase inhibitor

PDGFR

Platelet-derived growth factor receptor

PDGF

Platelet-derived growth factor

c-Fms

Colony-stimulating factor 1 receptor

MCSF

Macrophage colony-stimulating factor

CFA

Complete Freund’s adjuvant

TNF

Tumor necrosis factor

IL

Interleukin

CNS

Central nervous system

FCS

Fetal calf serum

NEAA

Non-essential amino acids

LFB

Luxol fast blue

HBSS

Hank’s buffered salt solution

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Oliver Crespo
    • 1
    • 2
  • Stacey C. Kang
    • 1
  • Richard Daneman
    • 5
  • Tamsin M. Lindstrom
    • 1
    • 2
  • Peggy P. Ho
    • 3
  • Raymond A. Sobel
    • 4
  • Lawrence Steinman
    • 3
  • William H. Robinson
    • 1
    • 2
  1. 1.Division of Immunology and Rheumatology, Department of MedicineStanford University School of MedicineStanfordUSA
  2. 2.VA Palo Alto Health Care SystemPalo AltoUSA
  3. 3.Department of Neurological Sciences and PediatricsStanford UniversityStanfordUSA
  4. 4.Department of PathologyStanford University School of MedicineStanfordUSA
  5. 5.Department of Developmental BiologyStanford University School of MedicineStanfordUSA