Hori S, Havaux X, Rubay R, Latinne D, Bazin H, Gianello P
Laboratory of Experimental Surgery, University of Louvain Medical School, Brussels, Belgium.
Transplantation. 1997 Jun 15;63(11):1554-61. doi: 10.1097/00007890-199706150-00003.
Heterotopic guinea pig (GP) cardiac xenografts (XG) are hyperacutely rejected within minutes when transplanted into rats.
In this GP to rat cardiac XG model, we studied the effect on graft survival of a short cold preservation time (1 hr at 4 degrees C) in the presence or absence of rat anti-GP IgM preformed antibodies. The complete depletion of circulating IgM was obtained by two intraperitoneal injections of anti-rat IgM monoclonal antibody (MARM-4) on preoperative days -3 and -1.
When the GP cardiac XG was cold preserved for 1 hr before transplantation, the mean graft survival time (MST) was 13.5+/-2.8 min, whereas without previous cold preservation, the MST was significantly prolonged to 51.5+/-12.3 min (P<0.001). Interestingly, the complete depletion of preformed circulating IgM before grafting significantly prolonged the MST of a cold-preserved XG to 37.1+/-11.3 min in comparison with a nondepleted recipient of a cold-preserved XG (P<0.02), but did not prolong the graft survival of a XG that was not cold preserved (42.5+/-14.1 min). To assess the effect of cold preservation and/or ischemia reperfusion, we intravenously injected a superoxide-dismutase mimetic (EUK-134) just before transplantation of a cold-preserved XG. This antioxidant regimen improved the MST from 13.5+/-2.8 min to 35.3+/-7.3 min (P<0.001). These results clearly suggested that either preservation lesions or preformed IgM are capable of accelerating the loss of the cardiac graft function, but also that the presence of preformed IgM seems to be especially deleterious when the cardiac XG has previously been ischemically injured. Analyzing the histological data, we also observed that the prompt cessation of cardiac function seen in cold-preserved grafts was uniformly associated with massive interstitial hemorrhage, thereby suggesting a particular susceptibility of the GP cardiac XG to cold preservation. To assess the effect of preservation on the GP cardiac function in a nonimmunological model, we performed syngeneic GP cardiac grafts and found that 1 hr of cold preservation provoked massive interstitial hemorrhage capable of promptly inducing the cessation of the heartbeat.
Overall, this study demonstrated that both ischemic lesions and immunological processes might induce the cessation of cardiac graft function in the GP to rat model and this cessation of graft function is probably often misinterpreted as a XG rejection only.
异位豚鼠心脏异种移植到大鼠体内时，数分钟内就会发生超急性排斥反应。
在这个豚鼠到大鼠的心脏异种移植模型中，我们研究了在存在或不存在大鼠抗豚鼠IgM预存抗体的情况下，短时间冷保存（4℃ 1小时）对移植物存活的影响。通过在术前第-3天和-1天腹腔内注射两次抗大鼠IgM单克隆抗体（MARM-4），实现循环IgM的完全清除。
当豚鼠心脏异种移植在移植前冷保存1小时时，平均移植物存活时间（MST）为13.5±2.8分钟，而未进行冷保存时，MST显著延长至51.5±12.3分钟（P<0.001）。有趣的是，与未清除循环IgM的冷保存异种移植受体相比，移植前循环IgM的完全清除显著延长了冷保存异种移植的MST至37.1±11.3分钟（P<0.02），但未延长未冷保存的异种移植的移植物存活时间（42.5±14.1分钟）。为了评估冷保存和/或缺血再灌注的影响，我们在冷保存的异种移植心脏移植前静脉注射了一种超氧化物歧化酶模拟物（EUK-134）。这种抗氧化方案将MST从13.5±2.8分钟提高到35.3±7.3分钟（P<0.001）。这些结果清楚地表明，保存损伤或预存IgM都能够加速心脏移植物功能的丧失，而且当心脏异种移植先前受到缺血性损伤时，预存IgM的存在似乎特别有害。分析组织学数据时，我们还观察到冷保存移植物中心脏功能的迅速停止与大量间质出血一致，从而表明豚鼠心脏异种移植对冷保存具有特殊的易感性。为了在非免疫模型中评估保存对豚鼠心脏功能的影响，我们进行了同基因豚鼠心脏移植，发现1小时的冷保存引发了大量间质出血，能够迅速导致心跳停止。
总体而言，本研究表明，缺血性损伤和免疫过程都可能在豚鼠到大鼠的模型中诱导心脏移植物功能停止，而这种移植物功能停止可能常常仅被误解为异种移植排斥反应。
