Gaca Jeffrey G, Appel James Z, Lukes Jeffrey G, Gonzalez-Stawinski Gonzalo V, Lesher Aaron, Palestrant Daniel, Logan John S, Love Stephanie D, Holzknecht Zoie E, Platt Jeffrey L, Parker William, Davis R Duane
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Transplantation. 2006 Jun 27;81(12):1686-94. doi: 10.1097/01.tp.0000226063.36325.02.
In contrast to renal or cardiac xenografts, the inhibition of complement using cobra venom factor (CVF) accelerates pulmonary xenograft failure. By activating C3/C5 convertase, CVF depletes complement while additionally generating C5a and other anaphylatoxins, to which pulmonary xenografts may be uniquely susceptible. The current study investigates the role of C5a in pulmonary xenograft failure in baboons.
Left orthotopic pulmonary xenografts using swine lungs expressing human CD46 were performed in baboons receiving: I) no other treatment (n=4), II) immunodepletion (n=5), and III) immunodepletion plus a single dose of mouse anti-human C5a monoclonal antibody (anti-C5a, 0.6 mg/kg administered intravenously) (n=3). The extent to which anti-C5a inhibits baboon C5a was assessed in vitro using a hemolytic reaction involving baboon serum and porcine red blood cells and by ELISA.
Baboons in Group III exhibited significantly prolonged xenograft survival (mean=722+/-121 min, P=0.02) compared to baboons in Group I (mean=202+/-24 min) and Group II (mean=276+/-79 min). Furthermore, baboons in Groups I and II experienced pronounced hemodynamic compromise requiring inotropic support whereas those in Group III remained hemodynamically stable throughout experimentation without the need for additional pharmacologic intervention.
These findings indicate that C5a exacerbates pulmonary xenograft injury and compromises recipient hemodynamic status. Moreover, blockade of anaphylatoxins, such as C5a, offers a promising approach for future investigations aimed at preventing pulmonary xenograft injury in baboons.
与肾或心脏异种移植不同，使用眼镜蛇毒因子（CVF）抑制补体可加速肺异种移植失败。通过激活C3/C5转化酶，CVF消耗补体，同时额外产生C5a和其他过敏毒素，肺异种移植可能对这些物质特别敏感。本研究调查了C5a在狒狒肺异种移植失败中的作用。
在接受以下处理的狒狒中进行使用表达人CD46的猪肺的左原位肺异种移植：I）不进行其他处理（n = 4），II）免疫清除（n = 5），以及III）免疫清除加单剂量小鼠抗人C5a单克隆抗体（抗C5a，静脉注射0.6 mg/kg）（n = 3）。使用涉及狒狒血清和猪红细胞的溶血反应以及酶联免疫吸附测定（ELISA）在体外评估抗C5a抑制狒狒C5a的程度。
与I组（平均 = 202±24分钟）和II组（平均 = 276±79分钟）的狒狒相比，III组的狒狒异种移植存活时间显著延长（平均 = 722±121分钟，P = 0.02）。此外，I组和II组的狒狒出现明显的血流动力学损害，需要使用正性肌力药物支持，而III组的狒狒在整个实验过程中血流动力学保持稳定，无需额外的药物干预。
这些发现表明C5a会加剧肺异种移植损伤并损害受体的血流动力学状态。此外，阻断过敏毒素，如C5a，为未来旨在预防狒狒肺异种移植损伤的研究提供了一种有前景的方法。
