Xenotransplantation refers to the transplantation of cells or whole organs from one species to another. Although the problems associated with this notion are great, so also are the promises. One primary problem is that of hyperacute rejection by the recipient of animal tissues due to preformed antibodies against oligosaccharides not found in primates. Genetic engineering of donor animals (typically pigs) can overcome this difficulty, but other problems of immune rejection remain. A further concern – one that has limited this field for decades, involves the potential for transfer of infections from one species to another. The development of safe techniques for cross-species transplantation could, however, render a range of tissues and whole organs available for transplantation. This would also overcome many current ethical difficulties alongside of addressing the shortage of human tissues for grafting. Routine organ transplantation from pigs to humans may soon become a clinical reality, as pig islets are currently being transplanted into humans in the course of a number of clinical trials.
Many attempts have been made to use animal tissues in man, dating back to blood transfusion experiments in the 17th century. Such grafts are, however, rejected immediately by a process called hyperimmune rejection. This is driven by the innate immune system which possesses preformed antibodies whose major target is galactose-α-1,3-galactose, an oligosaccharide not present in primates. The resulting reaction is an exaggerated version of the reaction seen when incompatible grafts are exchanged between humans.
Genetic manipulation of the donor animals can delete this antigen along with others that play a less prominent role, but further problems encountered in primates undergoing experimental transplantation include coagulopathies arising from incompatibilities between the pig and human systems. Other less well documented forms of chronic rejection have also been encountered.
Pig tissues such as heart valves and ligaments have been successfully used in humans for many years, but these do not contain viable cells. Whole organs from the pig are usually rejected rapidly in non-human primates despite immunosuppression. The worst outcomes are seen with lungs (usually less than 24 hour survival) and livers (about 1 week). Pig hearts (2 months) and kidneys survive better, but heavy proteinuria requiring albumin replacement is a uniform complication following renal replacement.
Pig islets for transplantation
Pig insulin is well tolerated by humans, and was widely used for many years. Islet grafts from pigs survive much better than whole organs in primate models, but portal vein infusion (the usual route in human islet grafts) is unsuccessful due to a response known as the immediate blood-mediated inflammatory reaction. To avoid this, a number of alternative graft sites are under consideration, including the gastric submucosal space and implantation into subcutaneous fat or muscle.
Despite these problems, non-human primates rendered diabetic by streptozotocin or pancreatectomy have been able to maintain normal glucose levels for several months. This has been aided by the observation that adult pig islets tend to lose expression of galactose-α-1,3-galactose. Neonatal pig islets do however retain the capacity to proliferate following transplantation. The combination of engineered porcine neonatal islets and light immunosuppression currently seems the most promising approach. Encapsulation would be an alternative. Grafts or capsules could be topped up as needed provided easily accessible sites for implantation can be identified.
Human viruses such as the Epstein–Barr virus or cytomegalovirus are readily transferred from donor to recipient in human transplantation, and could potentially cross species barriers in xenotransplants. Pig herds used for transplantation could however in theory be maintained free of such pathogens. On the other hand, it would be impossible to eradicate porcine retroviruses, since these are transmitted along with nuclear DNA.
There is evidently still a long way to go before xenotransplantation becomes a safe and effective clinical option, but recent progress suggests that the obstacles will one day be overcome. The pancreatic islets appear particularly suitable for human use, and their placement in immunologically privileged sites (i.e. locations inaccessible to immune effector cells), including encapsulation, may prove a realistic option.
^ Ekser B et al. Clinical xenotransplanation/:the next medical revolution? Lancet 2012;379(9816):672–83