Merion R M, Colletti L M
Department of Surgery, University of Michigan Medical School, Ann Arbor 48109.
Transplantation. 1990 May;49(5):861-8.
Hyperacute rejection following orthotopic liver transplantation remains an extremely unusual occurrence. In this study, we examined a porcine model of liver transplantation in which recipient animals were sensitized prior to transplantation with three serial full-thickness skin grafts. Three experimental groups were studied. Group I recipients (n = 6) were specifically sensitized against their liver donors with biweekly skin grafts followed by hepatic grafting. Group II recipients (n = 6) underwent third-party skin graft sensitization prior to liver transplantation. Group III recipients (n = 6) underwent liver grafting without sensitization. Mixed lymphocyte cultures were done before each skin graft and prior to transplantation. Lymphocytotoxic antibody (LCTA) titers were measured before the first skin graft, at weekly intervals thereafter, intraoperatively, and daily postoperatively until death. Intraoperative and postmortem liver biopsies were obtained in all recipients. Five of six recipients in Group I died within 4 hr of hepatic revascularization. The remaining animal survived for four days. Mean survival time in group I was 0 +/- 0.7 days. In contrast, MST in groups II and III were 4.0 +/- 1.2 and 6.2 +/- 1.3 days, respectively. The MST in group I was significantly shorter than in groups II and III (P less than 0.026 and P less than 0.005, respectively). There was no significant difference in survival between groups II and III. MLC reactivity between recipients and skin donors increased progressively following each skin graft, reaching a peak just prior to liver transplantation. LCTA titers also increased following each skin graft, reaching peak levels immediately prior to hepatic grafting. Intraoperative LCTA titers decreased within 2 min of graft revascularization and were undetectable within 4 hr. In group III (unsensitized recipients), MLC reactivity was low and at no time was LCTA detectable. Histologic examination of the livers from group I recipients showed parenchymal hemorrhage, endophlebitis, and neutrophil infiltration. Histologic examination of postmortem liver biopsies from animals in groups II and III revealed acute cellular rejection. In conclusion, hyperacute rejection resulting in graft failure and recipient death can be consistently produced in a porcine model of hepatic transplantation by donor-specific sensitization of the recipient. It is postulated that high titers of donor-specific antibody are required to exceed the liver's capacity for antibody absorption and elimination and produce the clinical picture of hyperacute rejection.
原位肝移植后的超急性排斥反应仍然极为罕见。在本研究中，我们检查了一种肝移植猪模型，其中受体动物在移植前通过三次连续的全层皮肤移植进行致敏。研究了三个实验组。第一组受体（n = 6）通过每两周一次的皮肤移植对其肝脏供体进行特异性致敏，然后进行肝脏移植。第二组受体（n = 6）在肝移植前接受第三方皮肤移植致敏。第三组受体（n = 6）未进行致敏就接受了肝脏移植。在每次皮肤移植前和移植前进行混合淋巴细胞培养。在第一次皮肤移植前、此后每周、术中以及术后每天直至死亡时测量淋巴细胞毒性抗体（LCTA）滴度。所有受体均进行了术中及死后肝脏活检。第一组的六只受体中有五只在肝脏血管再通后4小时内死亡。其余一只动物存活了四天。第一组的平均存活时间为0±0.7天。相比之下，第二组和第三组的平均存活时间分别为4.0±1.2天和6.2±1.3天。第一组的平均存活时间显著短于第二组和第三组（分别为P<0.026和P<0.005）。第二组和第三组之间的存活率无显著差异。每次皮肤移植后，受体与皮肤供体之间的混合淋巴细胞反应性逐渐增加，在肝移植前达到峰值。每次皮肤移植后LCTA滴度也增加，在肝脏移植前立即达到峰值水平。术中LCTA滴度在移植血管再通后2分钟内下降，4小时内检测不到。在第三组（未致敏受体）中，混合淋巴细胞反应性较低，且LCTA在任何时候都检测不到。第一组受体肝脏的组织学检查显示实质出血、静脉内膜炎和中性粒细胞浸润。对第二组和第三组动物死后肝脏活检的组织学检查显示为急性细胞排斥反应。总之，通过受体的供体特异性致敏，在猪肝移植模型中可以持续产生导致移植失败和受体死亡的超急性排斥反应。据推测，需要高滴度的供体特异性抗体才能超过肝脏吸收和消除抗体的能力，并产生超急性排斥反应的临床表现。
