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Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis
Ricardo T. Paniagua, … , Lawrence Steinman, William H. Robinson
Ricardo T. Paniagua, … , Lawrence Steinman, William H. Robinson
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2633-2642. https://doi.org/10.1172/JCI28546.
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Research Article Autoimmunity Article has an altmetric score of 7

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

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Abstract

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit–expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-α release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-α production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

Authors

Ricardo T. Paniagua, Orr Sharpe, Peggy P. Ho, Steven M. Chan, Anna Chang, John P. Higgins, Beren H. Tomooka, Fiona M. Thomas, Jason J. Song, Stuart B. Goodman, David M. Lee, Mark C. Genovese, Paul J. Utz, Lawrence Steinman, William H. Robinson

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Figure 1

Imatinib prevents and treats CIA.

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Imatinib prevents and treats CIA.
(A–D) Prevention. DBA/1 mice were admi...
(A–D) Prevention. DBA/1 mice were administered PBS (n = 15), 33 mg/kg imatinib (n = 15), or 100 mg/kg imatinib (n = 14) orally twice daily starting 1 day prior to induction of CIA. Severity of arthritis was assessed using a visual arthritis scoring system (A) and caliper measurements of paw thickness (B). The incidence of arthritis at the termination of the experiment (day 49) (C) and the mean weights of mice in each group (D) are presented. The data shown in A and B are from a representative of 3 independent experiments, each involving 14–15 mice per experimental arm. (E and F) Treatment. Following the development of clinical arthritis (average visual arthritis score of 4), DBA/1 mice with CIA were randomized and treated with PBS (n = 14), 33 mg/kg imatinib (n = 14), or 100 mg/kg imatinib (n = 14) orally twice daily, and disease was monitored using a visual arthritis scoring system (E) and paw thickness measurements (F). Values from the presented results are the mean ± SEM for this representative experiment. *P < 0.05, **P < 0.01 compared with PBS-treated mice.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 7 patents
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