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

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

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 5

Imatinib inhibits B cell proliferation and Ig production in vitro and autoreactive B cell epitope spreading in vivo.

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Imatinib inhibits B cell proliferation and Ig production in vitro and au...
(A) B cells from naive DBA/1 mice were stimulated with 50 μg/ml IgM or 5 μg/ml LPS in the presence of 0–10 μM imatinib. After 48 hours, B cells were pulsed with [3H]thymidine for 18 hours. Data represent mean cpm ± SEM of quadruplicates and are representative of 3 independent experiments. incorp., incorporation. (B) B cells stimulated with LPS (5 μg/ml) were cocultured with 0–10 μM imatinib, and IgM production was measured by ELISA. *P < 0.05, **P < 0.01, ***P < 0.001 compared with stimulated cells without imatinib. (C) Synovial array profiling of serum autoantibodies derived from mice with CIA treated with PBS (n = 7) or 100 mg/kg imatinib (n = 7) (day 49). Synovial microarrays containing candidate autoantigens in RA and CIA were incubated with 1:150 dilutions of mouse sera; autoantibody binding was detected with Cy3-labeled anti-mouse IgG/M secondary antibody; and arrays were scanned to quantify autoantibody binding to each antigen feature. SAM was applied to identify antigen features with statistical differences in autoantibody reactivity in samples derived from PBS-treated mice as compared with imatinib-treated mice (false discovery rate, 0.06). Cluster software was used to order results for the mice and the SAM-identified antigen features, and TreeView software was used to display the resulting clusters of autoantibody reactivity as a heatmap. Red represents positive reactivity, yellow intermediate reactivity, and blue lack of reactivity. Numbers in the key represent digital fluorescence intensity units.