Selective therapeutic control of C5a and the terminal complement complex by anti-C5 single-chain Fv in an experimental model of antigen-induced arthritis in rats
Selective therapeutic control of C5a and the terminal complement complex by anti-C5 single-chain Fv in an experimental model of antigen-induced arthritis in rats
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DOI：
10.1002/art.22492
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发表时间：
2007-04-01
影响因子：
--
通讯作者：
Tedesco, Francesco
中科院分区：
文献类型：
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作者：
Fischetti, Fabio;Durigutto, Paolo;Tedesco, Francesco
Objective.目的探讨补体末端复合物（TCC）在实验性抗原诱导性关节炎（AIA）发病中的作用及人源性抗C5单链抗体（scFv）的治疗作用。在AIA开始时注射两种不同的抗C5 scFv，一种抑制C5 a的释放和TCC的组装（TS-A 12/22），另一种选择性阻断TCC的形成（TS-A 8）。评价这些scFv对疾病严重程度的影响长达21天，并与注射不相关的scFv的影响进行比较。在C6缺乏和C6充足的PVG大鼠中也建立了AIA，以获得关于TCC在该模型中的作用的进一步信息。TS-A 12/22和TS-A 8被证明在减少关节肿胀、滑膜灌洗液中的细胞计数和肿瘤坏死因子α水平以及组织形态学变化的程度方面与不相关的scFv的效果相比是同样有效的。TS-A 12/22和TS-A 8阻止了C9的沉积，但没有阻止C3的沉积，证实了2scFv中和C5的能力。在AIA发作后施用2种抗C5 scFv也降低了疾病严重程度。C6缺乏的AIA大鼠的疾病活动性明显低于C6充足的大鼠。这2种人源抗C5单链抗体可作为治疗类风湿性关节炎的潜在药物。此外，TS-A 8在降低疾病严重程度方面与TS-A 12/22一样有效的发现表明TCC是AIA中观察到的关节炎症和损伤的主要原因。
Objective. To determine the role of the terminal complement complex (TCC) in the development of experimental antigen-induced arthritis (AIA) and the therapeutic effects of human anti-C5 single-chain Fv (scFv).Methods. Two different anti-C5 scFv, one that inhibits both release of C5a and assembly of the TCC (TS-A 12/22) and another that selectively blocks formation of the TCC (TS-A 8), were injected at the onset of AIA. The effects of these scFv on disease severity were evaluated for up to 21 days and compared with the effects of injection of an unrelated scFv. AIA was also established in C6-deficient and C6-sufficient PVG rats to obtain further information on the role of the TCC in this model.Results. TS-A 12/22 and TS-A 8 proved to be equally effective in reducing joint swelling, cell counts and tumor necrosis factor a levels in synovial lavage fluids, and the degree of histomorphologic changes compared with the effects of the unrelated scFv. TS-A 12/22 and TS-A 8 prevented the deposition of C9 but not that of C3, confirming the ability of the 2 scFv to neutralize C5. Administration of the 2 anti-C5 scFv after AIA onset also reduced disease severity. In C6-deficient rats with AIA, disease activity was reduced markedly compared with that in C6-sufficient rats.Conclusion. These 2 human anti-C5 scFv could represent potential therapeutic reagents to be used in patients with rheumatoid arthritis. In addition, the finding that TS-A 8 was as effective as TS-A 12/22 in reducing disease severity suggests that the TCC is mainly responsible for the joint inflammation and damage observed in AIA.