Xenotransplantation – has its time finally arrived?

Objectives

The continuing shortage of organs from deceased human donors prevents many patients with end-stage organ failure from receiving an organ transplant. Xenotransplantation, specifically the transplantation of organs from gene-edited pigs, might resolve the problem of organ supply.

Key findings

When transplanted into nonhuman primates, wild-type (i.e., genetically-unmodified) pig organs are rejected within minutes or hours by antibody-dependent complement-mediated injury and the effect of innate immune cells. With regard to the transplantation of pig kidneys and hearts (but not yet of livers or lungs), this response has largely been overcome by judicious gene-editing of the organ-source pig. Pigs with 10 or more gene edits are now available. However, the adaptive immune response to the graft still needs to be suppressed. Conventional immunosuppressive therapy, e.g., tacrolimus-based, is largely unsuccessful, whereas agents that block the CD40/CD154 T cell co-stimulation pathway are more effective.

Conclusions

The combination of gene-edited pig organs and co-stimulation blockade has extended life-supporting pig kidney survival to months or years and pig heart survival to a maximum of 9 months. However, consistent survival cannot yet be guaranteed and this needs to be achieved before formal clinical trials are initiated. Selection of patients for the initial clinical trials will be important. Patients aged 55–65 years with no or minimal comorbidities who are unlikely ever to receive a deceased human donor kidney would seem suitable candidates. Infants with life-threatening complex congenital heart disease who could be successfully bridged by a pig heart until an allograft became available would appear suitable candidates for pig heart transplantation.