Xenotransplantaion: Transplantation improves quality of life and saves tens of thousands of lives each year. However, the supply of human organs and tissues is insufficient to treat all patients who qualify for kidney, liver, islet cell, pancreas, heart, or lung transplantation.
These considerations provide a powerful impetus motivating early clinical introduction of cross species or “xeno” transplantation. Pigs have been developed as a potential xenograft source species based on various physiologic and logistical considerations.
Use of non-human primates is not feasible for a number of reasons, ethical concerns prominent among them, and because the risk of a nonhuman primate virus causing epidemic human disease is not acceptable.
Recently, a clinical islet xenograft trial involving 8 patients with diabetes and using porcine pancreatic cells has obtained provisional approval by New Zealand regulatory authorities.
Organ-specific considerations
Heart and Kidney:
Experimental xenotransplantation using pig hearts and kidneys in pharmacologically immunosuppressed primates has made important progress over the past two decades based primarily on genetic modification of source animals. Adding protective human “complement regulatory” genes to the pig confers significant protection from complement mediated organ xenograft injury.
Similarly, removing the most important pig carbohydrate antigen recognized by humans, Galactose 1,3α Galactose, by “knock-out” of the α-1, 3 galactosyltransferase gene is associated with the longest individual pig kidney (12 week) and heart (6 month) survivals yet achieved in nonhuman primates.
Liver Xenografts:
Timely support of patients with liver failure is a significant unmet clinical need. Extracorporeal perfusion using either wild-type or complement transgenic pig livers is associated with neurologic improvement in patients with hepatic failure and with successful bridging to transplant or recovery of the native liver.
GalT-KO pig livers, with or without additional genetic modifications, have not yet been tested, but may be promising for achieving therapeutic function and improved durability.
Extracorporeal liver perfusion in humans with hepatic failure would provide a relatively low-risk opportunity to study various immunologic and biochemical xeno interactions, and yield new knowledge potentially important to success in other areas of xenotransplantation.
Islet xenografts:
Significant progress has been made toward clinical trials of pig islet transplantation. Wild type porcine islets have reversed experimentally induced diabetes for up to 6 months in cynomolgus macaques and almost 9 months in rhesus monkeys. Although the immunosuppression used for these studies was more intensive than most clinicians and human patients would find acceptable.
These studies demonstrate consistent, prevalent long term insulin independence for the first time in pig-to-primate models. Preliminary data using islets from genetically modified pigs and with islet encapsulation suggest that a clinically acceptable regimen could soon be developed for clinical islet xenotransplantation.
Conclusion:
An important concern for clinical xenotransplantation is that a latent pig virus or another infectious agent could infect an immunosuppressed organ xenograft recipient and cause disease. Some experts consider it likely that infection of a xenograft recipient with a porcine organism will occur.
If this infection could be transmitted among humans by close contact or other means and particularly if the infection did not cause obvious symptoms, it could spread undetected into the community. It is encouraging that to date, infection with porcine endogenous retrovirus has not been detected in humans or other primates exposed to living pig cells and tissues, even with immunosuppression.