Sekine Chiyoko, Sugihara Takahiko, Miyake Sachiko, Hirai Hiroshi, Yoshida Mitsuaki, Miyasaka Nobuyuki, Kohsaka Hitoshi
Clinical Immunology, RIKEN Research Center of Allergy and Immunology, Yokohama, Japan.
J Immunol. 2008 Feb 1;180(3):1954-61. doi: 10.4049/jimmunol.180.3.1954.
Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis. Endogenous CDK inhibitors also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration of small molecules that inhibit CDK may or may not ameliorate arthritis. To address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and a newly synthesized CDK4/6-selective inhibitor were tested for antiarthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis mice with alvocidib suppressed synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed collagen-induced arthritis. Both small-molecule CDK inhibitors were effective in treating animal models of rheumatoid arthritis not by suppressing lymphocyte function. Thus, the two small-molecule CDK inhibitors ameliorated arthritis models in a distinctive way, compared with other immunosuppressive drugs.
关节内注射细胞周期蛋白依赖性激酶（CDK）抑制剂以抑制滑膜细胞的增殖，已被证明在类风湿关节炎动物模型的治疗中具有疗效。内源性CDK抑制剂也通过一条不依赖CDK的途径调节免疫功能。因此，全身给予抑制CDK的小分子药物可能会也可能不会改善关节炎。为了解决这个问题，我们测试了临床上已知可耐受用于治疗癌症的阿沃西地布（黄酮哌啶醇）以及一种新合成的CDK4/6选择性抑制剂的抗关节炎作用。在体外，它们抑制人和小鼠滑膜成纤维细胞的增殖而不诱导细胞凋亡。在体内，用阿沃西地布治疗胶原诱导的关节炎小鼠可抑制滑膜增生和关节破坏，而抗Ⅱ型胶原（CII）抗体的血清浓度以及对CII的增殖反应得以维持。即使在治疗性给药时，治疗也是有效的。治疗的小鼠在停药后会发生关节炎。因此，对CII的免疫反应未受损。同样的治疗改善了由K/BxN血清转移至淋巴细胞缺陷小鼠所诱导的关节炎。类似地，CDK4/6选择性抑制剂也抑制了胶原诱导的关节炎。这两种小分子CDK抑制剂在治疗类风湿关节炎动物模型时并非通过抑制淋巴细胞功能发挥作用。因此，与其他免疫抑制药物相比，这两种小分子CDK抑制剂以一种独特的方式改善了关节炎模型。
