During the past decade xenotransplantation, the use of animal organs, tissues or cells in humans, has made great advances. Due to the fact that more and more genetically modified pigs are available with genes to protect them from human immune response, has alleviated earlier problems in helping humans to accept such transplants. Dr Burcin Ekser and Dr David K C Cooper from the Thomas E Starzl Transplantation Institute at the University of Pittsburgh, PA, USA, and their team discuss the latest developments in a review published Online First by The Lancet.
In comparison to xenotransplantation of pig organs into non-human primates, research has found xenotransplantations of pig pancreatic islets into diabetic non-human primates to be more encouraging and a trial is currently ongoing in New Zealand. Although 60-80% of the transplanted islets are lost at the transplant site, i.e. in the hepatic portal vein, research continues to search for new transplantation sites and clinical trials of pig islet xenotransplantation could expand significantly over the next few years.
Neonatal (piglet) islets would be ideal for use in mass-transplantation programs as they are more economical to keep than adult pigs. The technology promises to be physiologically successful as a diabetic monkey survived for over one year supported only by pig islets.
Patients with type-1 diabetes could pose a possible problem for xenotransplantation as their autoimmune response could destroy the new grafts over time in the same way as the illness destroys the patients’ own pancreatic islets. One strategy could be to re-transplant those patients on a regular basis. Other strategies involve the research of ‘encapsulated’ islets, which are islets contained in a capsule that are shielded from the body’s immune system, so that immunosuppression is unnecessary. It is unknown if such islets can survive for extended periods of time although in this case retransplantation could be an alternative. The current trial in New Zealand is using encapsulated islets.
With millions of people worldwide suffering from neurological degenerative disease, another exciting option of xenotransplantation is the possibility of transplanting pigs neuronal cells. There are 8 million people in the USA alone who suffer from neurological degenerative disease, the most common one being Parkinson’s.
Previous trials revealed that transplantation of pig neuronal cells into non-human primates with a model of Parkinson’s disease significantly improved locomotor function. During the study some monkeys received genetically engineered human neural precursor cells and immunosuppressive therapy to prevent rejection. For some animals this was too much; they developed lymphoproliferative disease, which suggested that their immune system had been weakened excessively. The authors are still optimistic saying: “If this issue can be resolved, an early clinical trial would seem justified in patients whose disease is refractory to therapies.”
Other research areas include examining the possibility of transplanting pig liver and red blood cells as well as corneal transplants, which could help in tackling the enormous shortage of donor corneas in the developing world. Thrombic microangiopathy (TA) in the graft and systemic consumptive coagulopathy (SCC) in the recipient remain to be the biggest hurdles in the successful xenotransplantation of pig’s hearts and kidneys. In Thrombic microangiopathy clots of fibrin and red blood cells cause thrombosis in the blood vessels, whilst SCC, more common in kidney xenotransplants, deplets coagulation factors in the recipient causing spontaneous bleeding. Because of these problems, at this time the longest time of survival for pig organs in non-human primates varies from a few days in lung transplants to approximately 6-8 months in hearts transplants. Although research is still years away from conducting human trials of solid organ transplants of this nature, lifesaving transplants of a pig heart or liver could pose as an alternative solution until a human organ becomes available.
At present researchers are investigating strategies to incorporate human anticoagulant or antithrombotic genes into genetically modified pigs, and additional genes to regulate the human inflammatory response.
Ultimately there would also be a reduction in having to use extensive immunosuppressive drug therapies. To date genetic modifications have partly reduced T-cells responses, however these have to be improved by further genetic engineering. Researchers may also have to overcome physiological obstacles in solid organ transplantation but because there have not been any long-term successes, these obstacles are not yet known.
Since infections in pig herds are can commonly be controlled and cleared, safety does not appear to be an issue. This is supported by evidence to date, which shows that retroviruses carried by pigs do not pose a significant risk to human patients or close contacts.
The authors also discussed in terms of organs, that stages of other strategies are currently more advanced than xenotransplantation, such as left ventricular assist devices for cardiac support. However, they agree that given time, transplanting a pig’s heart will prove to be the better option compared to using a mechanical device.
In a concluding statement the authors say:
“Although remaining issues are delaying clinical implementation, experimental results obtained with pig islet, neuronal-cell, and corneal xenotransplantation have been encouraging. With new genetically modified pigs becoming available that are likely to improve the outcome of cellular and corneal xenotransplantation further, we believe that clinical trials will be justified within the next 2-3 years. No safety concerns that would prohibit such clinical trials have been reported…With regard to pig tissues and cells, as opposed to organs, it would seem that clinical xenotransplantation could soon become a reality.”
Written by Petra Rattue