論文

査読有り 国際誌
2016年1月

Cell cycle regulation therapy combined with cytokine blockade enhances antiarthritic effects without increasing immune suppression.

Annals of the rheumatic diseases
  • Tadashi Hosoya
  • ,
  • Hideyuki Iwai
  • ,
  • Yu Yamaguchi
  • ,
  • Kimito Kawahata
  • ,
  • Nobuyuki Miyasaka
  • ,
  • Hitoshi Kohsaka

担当区分
筆頭著者
75
1
開始ページ
253
終了ページ
9
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1136/annrheumdis-2014-205566

OBJECTIVE: Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression. METHODS: The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined. RESULTS: Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII. CONCLUSIONS: A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.

リンク情報
DOI
https://doi.org/10.1136/annrheumdis-2014-205566
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/25165034

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