权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

关节内基因转移细胞周期蛋白依赖性激酶抑制剂（CDKI），以抑制滑膜细胞周期已显示出疗效，在治疗类风湿性关节炎（RA）的动物模型。CDKIs还通过非CDKIs依赖性途径调节免疫功能。因此，全身施用抑制CDK的小分子可能改善关节炎。为了解决这个问题，测试了已知在临床上耐受用于治疗癌症的阿伏西地（flavopiridol）以及新合成的CDK 4/6选择性抑制剂的抗关节炎作用。在体外，它们抑制滑膜成纤维细胞的增殖而不诱导凋亡。在体内，用阿伏西地治疗胶原诱导的关节炎（CIA）抑制滑膜增生和关节破坏，同时维持抗II型胶原（CII）抗体的血清浓度。给药小鼠在给药终止后发生关节炎。因此，对CII的免疫应答未受损。相同的治疗改善了由K/BxN血清转移到淋巴细胞缺陷小鼠诱导的关节炎。类似地，CDK 4/6选择性抑制剂抑制CIA，即使在临床疾病发作后给药。两种小分子（sm）CDK抑制剂通过抑制滑膜细胞生长而不是免疫功能有效治疗RA动物模型。我们认为smCDK抑制剂有望成为一类新的抗风湿药物，抑制类风湿发病机制的不同阶段。