Abicht Jan-Michael, Kourtzelis Ioannis, Reichart Bruno, Koutsogiannaki Sophia, Primikyri Alexandra, Lambris John D, Chavakis Triantafyllos, Holdt Lesca, Kind Alexander, Guethoff Sonja, Mayr Tanja
Department of Anaesthesiology, Ludwig Maximilian University, Munich, Germany.
Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
Xenotransplantation. 2017 Jan;24(1). doi: 10.1111/xen.12262. Epub 2016 Sep 27.
The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3.
Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function. In the treatment group (n=5), the complement cascade was blocked at the level of C3 using Cp40, using diluted human blood. Untreated human and porcine blood was used for controls.
Throughout the perfusion, C3 activation was inhibited when Cp40 was used (mean of all time points: 1.11 ± 0.34% vs 3.12 ± 0.48% control activation; P<.01). Compared to xenoperfused controls, the cardiac index improved significantly in the treated group (6.5 ± 4.2 vs 3.5 ± 4.8 mL/min/g; P=.03, 180 minutes perfusion), while the concentration of lactate dehydrogenase as a maker for cell degradation was reduced in the perfusate (583 ± 187 U/mL vs 2108 ± 1145 U/mL, P=.02). Histological examination revealed less hemorrhage and edema, and immunohistochemistry confirmed less complement fragment deposition than in untreated xenoperfused controls.
Cp40 efficiently prevents C3 activation of the complement system, resulting in reduced cell damage and preserved function in wild-type porcine hearts xenoperfused ex vivo. We suggest that this compstatin analog, which blocks all main pathways of complement activation, could be a beneficial perioperative treatment in preclinical and in future clinical xenotransplantation.
补体系统在心脏移植后的急性异种反应中起关键作用。我们使用体外灌注模型研究Cp40（一种补体抑制素类似物，是C3水平上补体的有效抑制剂）的作用。
15个野生型猪心脏被取出，经心脏停搏液处理，并在冷缺血150分钟后进行体外再灌注。心脏在双心室工作心脏模式下接受刺激，以评估心脏灌注和功能。在治疗组（n = 5）中，使用Cp40在C3水平阻断补体级联反应，使用稀释的人血。未处理的人血和猪血用作对照。
在整个灌注过程中，使用Cp40时C3激活受到抑制（所有时间点的平均值：1.11±0.34% vs对照激活的3.12±0.48%；P<0.01）。与异种灌注对照组相比，治疗组的心脏指数显著改善（6.5±4.2 vs 3.5±4.8 mL/min/g；P = 0.03，灌注180分钟），而作为细胞降解标志物的灌注液中乳酸脱氢酶浓度降低（583±187 U/mL vs 2108±1145 U/mL，P = 0.02）。组织学检查显示出血和水肿较少，免疫组织化学证实补体片段沉积比未处理的异种灌注对照组少。
Cp40有效预防补体系统的C3激活，导致体外异种灌注的野生型猪心脏细胞损伤减少且功能得以保留。我们认为这种阻断补体激活所有主要途径的补体抑制素类似物，可能是临床前和未来临床异种移植中有价值的围手术期治疗方法。
