Suppression of osteoclastogenesis in rheumatoid arthritisby induction of apoptosis in activated CD4+T cells
Suppression of osteoclastogenesis in rheumatoid arthritisby induction of apoptosis in activated CD4+T cells
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DOI：
10.1002/art.11322
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发表时间：
2003-12-01
影响因子：
--
通讯作者：
Matsuno, H
中科院分区：
文献类型：
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作者：
Ogawa, Y;Ohtsuki, M;Matsuno, H
Objective.研究抗人Fas单克隆抗体（mAb）对类风湿关节炎（RA）破骨细胞生成的抑制作用。对于体外分析，来源于外周血单核细胞的活化的CD 4 + T细胞未处理或用人源化抗人Fas mAb（R-125224）处理并与人单核细胞共培养。在第12天，计数抗酒石酸酸性磷酸酶（TRAP）阳性多核细胞的数量。对于体内分析，将源自人RA血管翳的组织与牙本质切片一起皮下植入SCID小鼠的背部（SCID-HuRAg-pit模型）。R-125224每周静脉给药一次，持续3周。取出种植体组织和牙本质切片，分析牙本质切片上形成的小凹。在体外，活化的CD 4 + T细胞和外周血单核细胞共培养诱导破骨细胞生成。当用R-125224处理活化的CD 4 + T细胞时，TRAP阳性多核细胞的数量减少。我们建立了一种新的监测破骨细胞生成的动物模型SCID-HuRAg-pit。我们发现，在该模型中，R-125224处理后，种植牙本质切片上形成的凹坑数量显著减少，种植RA滑膜组织中的淋巴细胞数量显著减少。这是第一个研究证明抗人Fas单克隆抗体通过诱导T细胞凋亡对RA滑膜组织中破骨细胞生成的抑制作用。在抑制炎症和骨破坏方面，诱导浸润淋巴细胞凋亡可能是RA的一种有用的治疗策略。
Objective. To examine the suppressive effect of anti-human Fas monoclonal antibody (mAb) on osteoclastogenesis in rheumatoid arthritis (RA) both in vitro and in vivo.Methods. For in vitro analysis, activated CD4+ T cells derived from peripheral blood mononuclear cells were left untreated or were treated with humanized anti-human Fas mAb (R-125224) and cocultured with human monocytes. On day 12, the number of tartrateresistant acid phosphatase (TRAP)-positive multinucleated cells was counted. For in vivo analysis, tissue derived from human RA pannus was implanted with a slice of dentin subcutaneously in the backs of SCID mice (SCID-HuRAg-pit model). R-125224 was administered intravenously once a week for 3 weeks. The implanted tissue and dentin slice were removed, and the pits formed on the dentin slice were analyzed.Results. In vitro, coculture of activated CD4+ T cells and peripheral monocytes induced osteoclastogenesis. The number of TRAP-positive multinucleated cells was reduced when activated CD4+ T cells were treated with R-125224. We established a new animal model for monitoring osteoclastogenesis, SCID-HuRAg-pit. We found that with R-125224 treatment, the number of pits formed on the implanted dentin slices was significantly reduced and the number of lymphocytes in the implanted RA synovial tissue was dramatically reduced in this model.Conclusion. This is the first study to demonstrate the suppressive effect of anti-human Fas mAb on osteoclastogenesis in RA synovial tissues through the induction of T cell apoptosis. Induction of apoptosis of infiltrated lymphocytes could be a useful therapeutic strategy for RA, in terms of suppressing both inflammation and bone destruction.