Local immunomodulation as a new approach to ABO-incompatible liver transplantation

ABO血型不合通常被认为是肝移植的禁忌症，因为供体血型抗原的预形成抗体会引起严重的排斥反应，并伴有高发生率的胆管和血管并发症。本研究旨在探讨移植物免疫调节对大鼠肝移植体液排斥反应的影响。我们通过供体品系（BN）皮肤移植建立了致敏受体（刘易斯）。这些受体在30天内通过体液排斥反应排斥来自BN大鼠的肝移植物。排斥肝的病理结果显示广泛的出血性坏死伴器官内血栓形成，这与临床ABO血型不合肝移植后移植失败的情况相似。我们开发了一种新的门静脉内持续输注药物的技术，采用渗透泵。免疫调节剂，包括前列腺素E1，布地奈德，和加贝酯甲磺酸，移植后14天内注入。前列腺素E1通过血管舒张作用改善微循环，并抑制血小板聚集。布地奈德是一种新开发的类固醇，通过门静脉循环完全代谢。加贝酯甲磺酸盐是一种常用于全身性DIC的蛋白酶抑制剂，也抑制血小板聚集、凝血酶和其他凝血因子。这些局部免疫调节作用可改善排斥反应的程度，延长受体的生存期。我们的研究结果表明，这种新的概念，门静脉内输注治疗有很强的潜力，突破ABO血型障碍的肝移植，并提供了更大的机会，肝移植这些患者。

ABO-incompatibility is usually regarded as contraindication of liver transplantation, because preformed antibodies to donor-blood group antigen induce severe rejection with a high-rate of bile duct and vascular complications. The aim of this study is to investigate the effects of graft immunomodulation on humoral rejection in rat liver transplant model. We established presensitized recipients (Lewis) by donor-strain (BN) skin grafting. These recipients reject the liver graft from the BN rat within 30 days by humoral rejection. Pathologic findings of the rejected liver showed wide spread hemorrhagic necrosis with intra-organ thrombosis, which is similar to those seen in the failed graft after clinical ABO-incompatible liver transplantation. We developed new technique of continuous intra-portal drug infusion in the rat model, using osmotic pump. The immunomodulatory agents, including prostaglandin E1, budesonide, and gabexate mesilate, was infused intraportally for 14 days after transplantation. Prostaglandin E1 improves microcirculation through vasodilating effect and inhibits platelet aggregation. Budesonide is the newly developed steroid which is completely metabolyzed through portal circulation. Gabexate mesilate, a protease inhibitor commonly used for systemic DIC, inhibits platelet aggregation, thrombin, and other coagulation factors as well. These local immunomodulation improved the degree of rejection, and tended to prolong the recipient survival. Our results shows that this new concept of intra-portal infusion therapy has a strong potential to break through the ABO-blood group barriers in liver transplantation, and to provide much greater opportunity for liver transplantation for these patients.