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OP0105 Pyrazole-Anilide Derivatives, A New Class of Immunomodulator Which Inhibits IL-17 Production, Ameliorate CIA and Psoriasis-Like Dermatitis in Mice
  1. N. Seki,
  2. K. Shimano,
  3. T. Kondou,
  4. M. Murase,
  5. M. Mitamura,
  6. H. Kataoka,
  7. K. Sugahara,
  8. H. Nakamura,
  9. M. Yamada
  1. Pharmacology Research Laboratory I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

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

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