OP0105 Pyrazole-Anilide Derivatives, A New Class of Immunomodulator Which Inhibits IL-17 Production, Ameliorate CIA and Psoriasis-Like Dermatitis in Mice. (10th June 2014)

• Record Type: Journal Article
• Authors: Seki, N.; Shimano, K.; Kondou, T.; Murase, M.; Mitamura, M.; Kataoka, H.; Sugahara, K.; Nakamura, H.; Yamada, M.
• Is Part Of: Annals of the rheumatic diseases. Volume 73:Supplement 2(2014)
• Page Start: 100
• Page End: 101
• Publication Date: 2014-06-10
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2014-eular.3054
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Interleukin (IL)-17 is a pro-inflammatory cytokine produced by various types of cells including CD4 T cells which are categorized as a new subset called Th17 cells. The anti-IL-17A antibodies showed the effectiveness in a clinical trial for rheumatoid arthritis and psoriasis. We have discovered new pyrazole-anilide derivatives (compound A, B and C) which inhibited IL-17 production from mouse CD4 T cells. Objectives: We examined the effect of compounds on production of IL-17 and pro-inflammatory cytokines from mouse and human T cells. Furthermore, we evaluated the effect of compounds on autoimmune disease models in mice. Methods: In vitro: Mouse and human peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3 antibody for 72h. The concentration of pro-inflammatory cytokines in the culture supernatants was determined by BD™ Cytometric Beads Array. In vivo: Type II collagen-induced arthritis (CIA) was induced by immunization with an emulsion of bovine type II collagen (CII) and Freund's complete adjuvant (FCA) to the tail base of DBA/1J mice. For psoriasis-like dermatitis, imiquimod (IMQ) was topically applied to the ear of C57BL/6 mice every day for 8 days. Results: Compound A, B and C have a potent inhibitory activity for IL-17 production in antigen- specific mouse memory CD4 T cells and mouse Th17 cells. Moreover, compound B significantly inhibited IL-17 production from mouse and human PBMCs by anti-CD3 antibody stimulation with IC50 value of 600 and 2897 nM, respectively. In mouse CIA, the prophylactic treatment with compound A at 1 to 10 mg/kg showed a significant and dose-dependent inhibitory effect on arthritis score and joint destruction. When compound B and tofacitinib (CP-690, 550) were therapeutically administered to mice with established CIA, the progression of arthritis were significantly inhibited by treatment of compound B or CP-690, 550 and the inhibitory effect of compound B was comparable with that of the CP-690, 550. In this study, a treatment of CP-690, 550 decreased the number of NK cells in peripheral blood, however compound B did not affect NK cell counts. The mRNA expression level of IL-17 was markedly elevated in mouse hind paws accompanying with the development of CIA. By contrast, the mRNA expression level of IL-17 was significantly lower in groups given compound B as compared with a control group. Draining lymph node -T cells from CIA mice produced a significant amount of IL-17 by stimulation of CII. Compound B significantly inhibited this IL-17 production. Moreover, in the IMQ-induced psoriasis-like dermatitis, oral administration of compound C (3 and 10 mg/kg) inhibited an increase of the ear thickness. The inhibitory effect of compound C on IMQ-induced dermatitis was comparable with that of anti-mouse IL-17 antibody (200 μg/mouse). Conclusions: The new pyrazole-anilide derivatives ameliorated CIA and psoriasis-like dermatitis in mice. These compounds decreased the IL-17 mRNA expression level in hind paws of CIA mice and inhibited the antigen-induced IL-17 production from CII specific-T cells. Moreover, these compounds inhibited the IL-17 production from human T cells stimulated with anti-CD3 antibody. These results suggest that these compounds have a potential therapeutic efficacy for rheumatoid arthritis and psoriasis. Disclosure of Interest: None declared DOI: 10.1136/annrheumdis-2014-eular.3054