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Erschienen in: Journal of Clinical Immunology 6/2011

01.12.2011

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

verfasst von: Oliver Crespo, Stacey C. Kang, Richard Daneman, Tamsin M. Lindstrom, Peggy P. Ho, Raymond A. Sobel, Lawrence Steinman, William H. Robinson

Erschienen in: Journal of Clinical Immunology | Ausgabe 6/2011

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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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Metadaten
Titel
Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis
verfasst von
Oliver Crespo
Stacey C. Kang
Richard Daneman
Tamsin M. Lindstrom
Peggy P. Ho
Raymond A. Sobel
Lawrence Steinman
William H. Robinson
Publikationsdatum
01.12.2011
Verlag
Springer US
Erschienen in
Journal of Clinical Immunology / Ausgabe 6/2011
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-011-9579-6

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