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

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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.

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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

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Acknowledgments

We thank Ben Barres’ group, in particular Maria Fabian, for kindly providing the rat primary astrocytes. We also thank Jane Eaton for providing guidance through the histopathology tissue-staining process. This work was supported by National Institutes of Health (NIH) National Heart Lung and Blood Institute contract N01-HV-00242, NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR-054822, and Veterans Affairs Health Care System funding awarded to WHR. OC received funding from the NIH training grant 5 T32 AI07290 for Molecular and Cellular Immunobiology.

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Correspondence to William H. Robinson.

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Crespo, O., Kang, S.C., Daneman, R. et al. Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis. J Clin Immunol 31, 1010–1020 (2011). https://doi.org/10.1007/s10875-011-9579-6

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  • DOI: https://doi.org/10.1007/s10875-011-9579-6

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