Overcoming the barriers to xenotransplantation: prospects for the future

Abstract

Cross-species transplantation (xenotransplantation) has immense potential to solve the critical need for organs, tissues and cells for clinical transplantation. The increasing availability of genetically engineered pigs is enabling progress to be made in pig-to-nonhuman primate experimental models. Potent pharmacologic immunosuppressive regimens have largely prevented T-cell rejection and a T-cell-dependent elicited antibody response. However, coagulation dysfunction between the pig and primate is proving to be a major problem, and this can result in life-threatening consumptive coagulopathy. This complication is unlikely to be overcome until pigs expressing a human 'antithrombotic' or 'anticoagulant' gene, such as thrombomodulin, tissue factor pathway inhibitor or CD39, become available. Progress in islet xenotransplantation has been more encouraging, and diabetes has been controlled in nonhuman primates for periods in excess of 6 months, although this has usually been achieved using immunosuppressive protocols that might not be clinically applicable. Further advances are required to overcome the remaining barriers.

Keywords: antibodies; antipig; coagulation; consumptive coagulopathy; genetically engineered; nonhuman primate; pig; xenotransplantation.

Figure 1. Summary of the major known immunologic barriers to pig-to-primate organ transplantation, as exemplified in the transplanted pig heart

In hyperacute rejection, the graft develops microvascular thrombi, beginning in the venules. Occlusion of the vessels leads to rupture with interstitial hemorrhage and edema. Some cells of the innate immune system, such as neutrophils and macrophages, may be present. The appearance in acute humoral xenograft rejection is similar, although infiltration by cells of the innate immune system is more pronounced. Isolated acute cellular rejection is very rare, but T cells can be seen when thrombotic microangiopathy develops. The role of T cells in the development of thrombotic microangiopathy is uncertain and controversial. Reproduced with permission from [72].

Figure 2. Progress in the results of pig heterotopic heart transplantation in baboons (1986–2005)

(A) Survival (in hours) of selected pig heterotopic heart grafts in baboons (1986–1996). (B) Survival (in days) of selected pig heterotopic heart grafts in baboons (1997–1999). (C) Survival (in weeks) of selected pig heterotopic heart grafts in baboons (2000–2005). CVF: Cobra venom factor; EIA: Extracorporeal immunoadsorption; GTKO: α1,3-galactosyltransferase gene-knockout; hDAF: Pig transgenic for human decay-accelerating factor; IS: Pharmacologic immunosuppressive therapy; KIA: Prior pig kidney perfusion to deplete antipig antibodies; SPX: Splenectomy; TIR: Tolerance-inducing regimen; WT: Wild-type. Reproduced with permission from [72].