Hypothermic Oxygenated Perfusion (HOPE) Downregulates the Immune Response in a Rat Model of Liver Transplantation

Abstract

OBJECTIVE: To evaluate the impact of a novel oxygenated perfusion approach on rejection after orthotopic liver transplantation (OLT). BACKGROUND: Hypothermic oxygenated perfusion (HOPE) was designed to prevent graft failure after OLT. One of the mechanisms is downregulation of Kupffer cells (in situ macrophages). We, therefore, designed experiments to test the effects of HOPE on the immune response in an allogeneic rodent model of nonarterialized OLT. METHODS: Livers from Lewis rats were transplanted into Brown Norway rats to induce liver rejection in untreated recipients within 4 weeks. Next, Brown Norway recipients were treated with tacrolimus (1 mg/kg), whereas in a third group, liver grafts from Lewis rats underwent HOPE or deoxygenated machine perfusion for 1 hour before implantation, but recipients received no immunosuppression. In a last step, low-dose tacrolimus treatment (0.3 mg/kg) was assessed with and without HOPE. RESULTS: Allogeneic OLT without immunosuppression led to death within 3 weeks after nonarterialized OLT due to severe acute rejection. Full-dose tacrolimus prevented rejection, whereas low-dose tacrolimus led to graft fibrosis within 4 weeks. HOPE treatment without immunosuppression also protected from lethal rejection. The combination of low-dose tacrolimus and 1-hour HOPE resulted in 100% survival within 4 weeks without any signs of rejection. CONCLUSIONS: We demonstrate that allograft treatment by HOPE not only protects against preservation injury but also impressively downregulates the immune system, blunting the alloimmune response. Therefore, HOPE may offer many beneficial effects, not only to rescue marginal grafts but also by preventing rejection and the need for immunosuppression.

Short, Cool, and Well Oxygenated – HOPE for Kidney Transplantation in a Rodent Model

“…Second, endischemic HOPE treatment of DCD kidneys does not provoke relevant ROS release, in contrast to normothermic perfusion, corresponding to earlier results in livers. 11 Cellular energy charge is significantly higher uploaded than normothermic perfusion. Third, normothermic perfusion of cold-stored DCD kidneys induces an inflammatory milieu during perfusion and triggers reperfusion injury by release of ROS already before implantation.…”

“…According to previous publications, [9][10][11] we opted for a rodent DCD kidney transplant model, with induction of cardiac arrest by incision of the diaphragm without prior heparinization or vessel clamping. We applied 30 minutes of asystolic donor warm ischemia time in all experimental groups and used an established orthotopic model of kidney transplantation for recipients.…”

“…[4][5][6][7] In this context, our group developed a short-term 1 to 2-hour Hypothermic Oxygenated Perfusion (HOPE), applied after cold storage in liver transplantation. [8][9][10][11][12][13] In various animal transplant models, we showed a high protective effect of HOPE. [8][9][10][11] In addition, recent human application of HOPE rescued extended DCD livers, exposed to long donor warm ischemia, 12 and was superior than matched, un-perfused DCD liver grafts.…”

“…[8][9][10][11][12][13] In various animal transplant models, we showed a high protective effect of HOPE. [8][9][10][11] In addition, recent human application of HOPE rescued extended DCD livers, exposed to long donor warm ischemia, 12 and was superior than matched, un-perfused DCD liver grafts. 13 On the basis of the success of HOPE in livers, we aimed to test HOPE in kidneys.…”

Current perspectives in transplant medicine: hypothermic oxygenated perfusion

“…Thus, "oxygenated" HMP can avoid oxidative stress for the donor organ. 13,14 Interestingly, three different preclinical studies using a porcine kidney transplant model found a difference in the effects of oxygenation in MP depending on whether the organ was procured from a heart-beating donor or from a DCD donor. When heart-beating donors were used oxygenated MP was actually inferior to anoxic MP as evidenced in the lower creatinine clearance in the oxygenated group.…”