Xenotransplantation (the use of animal organs, tissues or cells in humans) has made great strides in the past decade. Previous difficulties in helping a human host accept such transplants have been overcome thanks to the increasing availability of genetically modified pigs equipped with genes to protect them from the human immune response. In a Review published Online First by The Lancet, Drs Burcin Ekser and David K C Cooper, Thomas E Starzl Transplantation Institute, University of Pittsburgh, PA, USA, and colleagues discuss the latest developments in this exciting and fast-moving field.
Results from xenotransplantation of pig pancreatic islets into diabetic non-human primates are much more encouraging than are those of xenotransplantation of pig organs. Clinical trials of pig islet xenotransplantation could expand substantially over the next few years, and a trial is currently ongoing in New Zealand. The main problems confronting this technique are that 60 % to 80% of the transplanted islets are lost at the transplant site (the hepatic portal vein) so new sites for transplantation are being researched. Ideally, neonatal (piglet) islets would be used in any mass-transplantation programme, since it would be much more expensive to keep adult pigs for this purpose. A diabetic monkey has survived for more than 1 year supported only by pig islets, suggesting that the technique will be physiologically successful. A potential problem arises for type 1 diabetes patients, whose autoimmune response could destroy the new grafts over time (just as the patients' own pancreatic islet cells were destroyed). However, regular re-transplantation could occur if this happened. Other researchers are studying 'encapsulated' islets. These islets are shielded from the body's immune system in a capsule, so that immunosuppression is not necessary. However, retransplantation could be carried out if this happened. Other researchers are studying 'encapsulated' islets, which are shielded from the body's immune system in a capsule so that immunosuppression is not necessary. However, whether such islets can survive for long periods is not known (although, as above, retransplantation could be done when required). The ongoing trial in New Zealand is using encapsulated islets.
Another exciting area in this field is possible transplantation of pig neuronal cells. Millions of people around the world (8 million in the USA) have neurological degenerative diseases, of which Parkinson's disease is one of the most common. Early trials have shown that transplantation of pig neuronal cells into non-human primates with a model of Parkinson's disease greatly improves locomotor function. To prevent rejection, some monkeys received genetically engineered human neural precursor cells, as well as immunosuppressive therapy. This proved too much for some animals, who developed lymphoproliferative disease, suggesting that their immune system had been weakened excessively. But the authors say: "If this issue can be resolved, an early clinical trial would seem justified in patients whose disease is refractory to therapies." Other research is analysing the possibility of pig liver and red blood cell transplants, and also corneal transplants that could help to address the huge shortage of donor corneas in the developing world.
The main remaining obstacles to successful xenotransplantation of pig organs, such as the heart and kidney, are thrombic microangiopathy (TA) in the graft and systemic consumptive coagulopathy (SCC) in the recipient. In TA, clots of fibrin and red blood cells cause thrombosis in the graft blood vessels. SCC is more common in kidney xenotransplants, and is characterised by depletion of coagulation factors in the recipient, leading to spontaneous bleeding. These problems mean that the longest survival time for pig organs in non-human primates to date ranges from a few days for lungs to around 6-8 months for hearts, and trials of solid organ transplants of this nature in humans are likely to be several years away. However, life-saving transplants of a pig liver or heart could be justified as a bridge until a human organ becomes available. Researchers are currently working on ways to incorporate human anticoagulant or antithrombotic genes into genetically modified pigs, as well as additional genes to modulate the human inflammatory response. Ideally, the need for extensive immunosuppressive drug regimens would also be reduced; genetic modifications to date have reduced the T-cell response in part, but further genetic engineering will be necessary to improve this. There may also be physiological barriers to solid organ transplantation, which are as yet unknown due to the lack of long-term success. Safety appears not be an issue, since it is possible to clear pig herds of relevant infections and evidence to date shows that the retroviruses carried by pigs do not pose a substantial risk to the human patient or his or her close contacts. Regarding organs, the authors discuss that some other techniques (for example, left ventricular assist devices for cardiac support) are at a more advanced stage than xenotransplantation, but believe that eventually the transplantation of a pig heart will prove preferable to a mechanical device.
The authors conclude: "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 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."
Dr Burcin Ekser, Thomas E Starzl Transplantation Institute, University of Pittsburgh, PA, USA. T) +1 412-708-5751 E) ekserb@upmc.edu
Dr David K C Cooper, Thomas E Starzl Transplantation Institute, University of Pittsburgh, PA, USA. T) +1 412-383-6961 E) cooperdk@upmc.edu
Journal
The Lancet