Recent advances in understanding xenotransplantation: implications for the clinic

Abstract

The results of organ and cell allotransplantation continue to improve, but the field remains limited by a lack of deceased donor organs. Xenotransplantation, for example, between pig and human, offers unlimited organs and cells for clinical transplantation. The immune barriers include a strong innate immune response in addition to the adaptive T-cell response. The innate response has largely been overcome by the transplantation of organs from pigs with genetic modifications that protect their tissues from this response. T-cell-mediated rejection can be controlled by immunosuppressive agents that inhibit costimulation. Coagulation dysfunction between the pig and primate remains problematic but is being overcome by the transplantation of organs from pigs that express human coagulation-regulatory proteins. The remaining barriers will be resolved by the introduction of novel genetically-engineered pigs. Limited clinical trials of pig islet and corneal transplantation are already underway.

Keywords:

• genetically-engineered pig
• immunobiology
• islets pig
• organs pig
• xenotransplantation

Financial & competing interests disclosure

We thank our many colleagues at the University of Pittsburgh, Allegheny-Singer Research Institute, and Revivicor Inc. (Blacksburg, VA) who have contributed to our own studies included in this review. Work on xenotransplantation in the Thomas E Starzl Transplantation Institute of the University of Pittsburgh is supported in part by NIH grants #U19 AI090959, #U01 AI068642, and # R21 A1074844, and # PO1 HL107152 and by Sponsored Research Agreements between the University of Pittsburgh and Revivicor, Blacksburg, VA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• It will be necessary to demonstrate consistent 6-month recipient survival (with evidence that some recipients survive for 12 months) after life-supporting organ (heart or kidney) transplantation in 5–10 consecutive pig-to-NHP experiments before a clinical trial could be justified.

• This must be achieved in the absence of the development of graft atherosclerosis or other severe histopathological injury and without major complications related to the need for intensive systemic immunosuppressive therapy.

• Perhaps less stringent milestones are necessary to warrant a clinical trial of pig islet transplantation.

• A bridging clinical trial of pig liver transplantation might be justified if life-supporting pig livers could consistently support NHPs for periods of 10–14 days in the absence of major complications, for example, severe thrombocytopenia, and with evidence of adequate pig hepatic function. Recipient and graft survival for 10–14 days would be sufficient to indicate that a patient in fulminant hepatic failure is likely to be supported by the pig liver long enough for a liver from a deceased human donor to be obtained.

• Even though NHPs provide a very poor model for the study of transfer of porcine endogenous retroviruses, there must be no evidence from studies in humans or NHPs that a clinical trial would be associated with a definitive risk of any other porcine infectious agent spreading into the human community.

Notes

^†Based on a table published in J Pathol (Cooper DKC, et al., 2015, in press), courtesy of Burcin Ekser MD, PhD.