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

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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.