New treatment of rheumatoid arthritis

类风湿性关节炎的新疗法

基本信息

批准号：
17390289
负责人：
KOHSAKA Hitoshi
金额：
$ 9.86万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Intra-articular gene transfer of cyclin-dependent kinase inhibitors (CDKI) to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis (RA). CDKIs also modulate immune function via a CDKindependent pathway. Accordingly, systemic administration of small molecules that inhibit CDK might ameliorate arthritis. In order to address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and also a newly synthesized CDK4/6-selective inhibitor were tested for anti-arthritic effects. In vitro, they inhibited proliferation of synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti- type II collagen (CII) antibodies were maintained. 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 CIA, even when administered after onset of clinical disease. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA by suppressing synovial cell growth but not immune function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis.

细胞周期蛋白依赖性激酶抑制剂（CDKI）抑制滑膜细胞循环的关节内基因转移已显示出在治疗类风湿关节炎动物模型（RA）方面的功效。 CDKIS还通过CDKINTEPENT途径调节免疫功能。因此，抑制CDK的小分子的全身给药可能会改善关节炎。为了解决这个问题，已知在临床治疗癌症上耐受耐受的Alvocidib（黄素寡醇），还测试了新合成的CDK4/6选择性抑制剂的抗关节炎作用。在体外，它们抑制了滑膜成纤维细胞的增殖而不诱导凋亡。在体内，维持了胶原蛋白诱导的关节炎（CIA）用ALVOCIDIB抑制的滑膜增生和关节破坏，而血清II型胶原蛋白（CII）抗体的浓度则保持了。治疗后治疗后患有关节炎。因此，对CII的免疫反应没有受损。 K/BXN血清转移到淋巴细胞缺陷小鼠引起的相同治疗可以改善关节炎。同样，即使在临床疾病发作后服用，CDK4/6选择性抑制剂也抑制了CIA。两个小分子（SM）CDK抑制剂均通过抑制滑膜细胞生长而不是免疫功能有效地治疗RA动物模型。我们认为，SMCDK抑制剂作为一种新的抗炎性药物有望抑制类风湿发病机理的独特阶段。