Comparative suppressive effects of tyrosine kinase inhibitors imatinib and nilotinib in models of autoimmune arthritis

Abstract

Imatinib and nilotinib are inhibitors that selectively target a set of protein tyrosine kinases, including abelson kinase (Abl), together with the chimeric oncoprotein, breakpoint cluster region-abelson kinase (Bcr-Abl), as well as stem cell factor receptor (KIT), platelet-derived growth factor receptor (PDGFR), discoidin domain receptor (DDR), and colony stimulating factor-1 receptor (CSF-1R). The aim of the present study was to investigate whether imatinib or nilotinib was effective against arthritis in the glucose-6-phosphate isomerase (GPI)-induced arthritis mouse model. Imatinib or nilotinib was administered orally to the arthritic mice at different time points. Efficacy was evaluated by visual scoring and by determining the production of anti-GPI antibody. Splenocytes from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro, and cytokine levels in the culture supernatants were analyzed. To investigate the effects of imatinib and nilotinib on T-cell proliferation, lymph node cells from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro. Interleukin (IL)-17 mRNA expression in the arthritic ankle joints from the onset of arthritis was analyzed by real-time polymerase chain reaction (PCR). The administration of imatinib from day 0 showed suppression of arthritis (P < 0.05), the administration of nilotinib from day 0 resulted in pronounced suppression of arthritis (P < 0.01), and that from day 7 showed significant inhibition of the progression of arthritis (P < 0.05). A reduction in anti-GPI antibodies was correlated with the therapeutic efficacy of imatinib, but not with that of nilotinib. Imatinib dose-dependently inhibited tumor necrosis factor (TNF)-α, IL-6, interferon (IFN)-γ, and IL-17 production by splenocytes in vitro, while nilotinib inhibited only IL-17 and IFN-γ production in a dose-dependent fashion. Imatinib at 3 μM exerted a mild antiproliferative effect on CD4+ T cells (P < 0.05), whereas imatinib at 10 μM and nilotinib at 3 and 10 μM demonstrated a marked antiproliferative effect (P < 0.01). The IL17 gene expression level on day 7 tended to be higher than that on day 14. These findings suggest that imatinib and nilotinib could prevent autoimmune arthritis, essentially via distinct mechanisms, in that imatinib inhibits both inflammatory and T-cell-derived cytokine production, whereas nilotinib suppresses T-cell-derived cytokine production. Imatinib and nilotinib could have therapeutic potential for rheumatoid arthritis (RA) and other inflammatory diseases.

Discoidin domain receptor 2 mediates collagen-induced activation of membrane-type 1 matrix metalloproteinase in human fibroblasts

“…Thus, DDR2 activation at the site may play a crucial role in joint destruction, and DDR2 is potentially a novel therapeutic target for RA. Previously administration of the tyrosine kinase inhibitor imatinib was shown to prevent arthritis development in mice (44–46). Imatinib was originally developed as an inhibitor for the oncogene BCR-ABL tyrosine kinase, and it is an approved drug for chronic myelogenous leukemia (47).…”

Neuroimmunological Blood Brain Barrier Opening in Experimental Cerebral Malaria

“…This notion is in agreement with earlier work showing that endothelial barrier stabilizing mediators such as sphingosine-1-phosphate (S1P) and angiopoietin-1 (Ang-1) regulate reversible paracellular and/or transcellular fluid transport mechanisms by opposing the action of permeability-increasing mediators such as platelet-activating factor (PAF), bradykinin, thrombin, histamine, and VEGF [101], [102]. However, FTY720 also inhibits T cell egress from lymph nodes, changing the dynamics of leukocyte recruitment to the brain, and imatinib is also known to directly affect T cell function [103], [104]. Studies are underway to determine if FTY720 and imatinib prevent ECM by modifying the immune response within the brain, rather than by directly effecting endothelial cell function, whether junctional integrity or vesicular transport.…”

SEA Antagonizes the Imatinib-Meditated Inhibitory Effects on T Cell Activation via the TCR Signaling Pathway

“…These agents have been recently used to treat autoimmune diseases, such as immune-mediated kidney injury and rheumatoid arthritis. Tyrosine kinase inhibitors (TKIs) are effective for the treatment of these diseases [31, 32]. …”