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 collageninduced 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.

Regulation of phagocyte migration and recruitment by Src-family kinases

“…In this context, it is worth noting that, although the issue of leukocyte migration was not specifically addressed in that study, imatinib mesylate (a c-Abl inhibitor formerly known as STI-571) was reported to be an effective treatment for a murine form of autoimmune arthritis [58].…”

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia

“…Rapid progression was confirmed morphologically 12 weeks after cell therapy in patient 1; this may have been related to imatinib (TKI) administration beginning from 5 weeks after cell infusion, given possible functional repression of T cells by TKI. [26][27][28][29][30] Interestingly and Arrows indicated the date of lentivirus transfection.…”

META060 inhibits multiple kinases in the NF-κB pathway and suppresses LPS – mediated inflammation in vitro and ex vivo

“…A number of potent kinase inhibitors (e. g., imatinib) employed to treat certain cancers have been shown to dramatically reduce arthritis symptoms [9]. Currently, approved cancer kinase inhibitor drugs to treat chronic inflammatory disease are limited due to their extreme potency against several kinases important in housekeeping functions, and hence causing severe adverse effects.…”

“…Protein kinases regulating the NF-kB pathway may be suitable targets for treating inflammation [7,8]. In support of this hypothesis, the multi-target kinase inhibitor imatinib (Gleevec ® ) is reported to be efficacious in treating rheumatoid arthritis [9], but with associated toxicities when used for long duration.…”