Fujisawa K, Asahara H, Okamoto K, Aono H, Hasunuma T, Kobata T, Iwakura Y, Yonehara S, Sumida T, Nishioka K
Division of Rheumatology and Immunology, Institute of Medical Science, St. Marianna University School of Medicine, Japan.
J Clin Invest. 1996 Jul 15;98(2):271-8. doi: 10.1172/JCI118789.
We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.
我们最近证实了类风湿关节炎（RA）患者滑膜中Fas介导的细胞凋亡，并提示这可能是导致RA病情缓解的一个因素。为了研究抗Fas单克隆抗体（mAb）诱导的细胞凋亡是否可能作为一种新的RA治疗策略发挥潜在作用，我们在RA动物模型——人类I型嗜T细胞白血病病毒（HTLV-1）tax转基因小鼠中，研究了抗Fas mAb（RK-8）对滑膜炎的影响。我们在此报告，向小鼠关节腔内注射抗Fas mAb可在48小时内改善爪肿胀和关节炎症状。免疫组织化学研究和体外培养研究表明，滑膜中35%的成纤维细胞、75%的单核细胞以及一些浸润的多形核白细胞通过抗Fas mAb发生凋亡。原位缺口末端标记分析和电子显微镜分析清楚地显示，抗Fas mAb给药后滑膜中的许多细胞被诱导凋亡。然而，局部注射抗Fas mAb并未产生全身副作用。结果表明，在HTLV-1 tax转基因小鼠的关节炎关节中注射抗Fas mAb可改善关节炎症状。这些发现提示，局部注射抗Fas mAb可能是治疗如RA等增殖性滑膜炎的一种有效治疗策略。
