title: 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.
authors.affiliation: Clinical Immunology, Advanced Biochemical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Akashi
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Kayo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Naoto
authors.initials: N
authors.lastname: Umeda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Taichi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Goto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Kaneo
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D000937:Antigen-Antibody Reactions / Q000187:drug effects / Q000276:immunology; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D001549:Benzamides; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000276:immunology; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology / Q000494:pharmacology; D000068877:Imatinib Mesylate; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D001549:Benzamides; D020381:Interleukin-17; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068877:Imatinib Mesylate; D005956:Glucose-6-Phosphate Isomerase; C498826:nilotinib