Division of Virology, Innsbruck Medical University, Innsbruck, Austria.
Leukemia. 2013 Nov;27(11):2200-8. doi: 10.1038/leu.2013.169. Epub 2013 Jun 13.
A main effector mechanism of rituximab (RTX) is the induction of complement-dependent cytotoxicity (CDC). However, this effector function is limited, because CLL cells are protected from complement-induced damage by regulators of complement activation (RCAs). A prominent RCA in fluid phase is factor H (fH), which has not been investigated in this context yet. Here, we show that fH binds to CLL cells and that human recombinant fH-derived short-consensus repeat 18-20 (hSCR18-20) interferes with this binding. In complement-based lysis assays, CLL cells from therapy-naive patients were differently susceptible to RTX-induced CDC and were defined as CDC responder or CDC non-responder, respectively. In CDC responders, but notably also in non-responders, hSCR18-20 significantly boosted RTX-induced CDC. Killing of the cells was specific for CD20(+) cells, whereas CD20(-) cells were poorly affected. CDC resistance was independent of expression of the membrane-anchored RCAs CD55 and CD59, although blocking of these RCAs further boosted CDC. Thus, inhibition of fH binding by hSCR18-20 sensitizes CLL cells to CDC and may provide a novel strategy for improving RTX-containing immunochemotherapy of CLL patients.
利妥昔单抗（RTX）的主要效应机制是诱导补体依赖性细胞毒性（CDC）。然而，这种效应功能是有限的，因为 CLL 细胞受到补体激活调节剂（RCAs）的保护，免受补体诱导的损伤。在液相中一种突出的 RCA 是因子 H（fH），但迄今为止尚未对此进行研究。在这里，我们表明 fH 与 CLL 细胞结合，并且人重组 fH 衍生的短共有重复序列 18-20（hSCR18-20）干扰这种结合。在基于补体的裂解测定中，来自未经治疗的患者的 CLL 细胞对 RTX 诱导的 CDC 具有不同的易感性，并分别定义为 CDC 应答者或 CDC 非应答者。在 CDC 应答者中，但值得注意的是在非应答者中，hSCR18-20 显著增强了 RTX 诱导的 CDC。细胞的杀伤是针对 CD20（+）细胞的，而 CD20（-）细胞则受到较差的影响。CDC 抗性与膜锚定 RCA CD55 和 CD59 的表达无关，尽管阻断这些 RCA 进一步增强了 CDC。因此，通过 hSCR18-20 抑制 fH 结合可使 CLL 细胞对 CDC 敏感，并可能为改善包含 RTX 的 CLL 患者免疫化学疗法提供新策略。
