Liver transplantation from animals. Hope and challenges explained by leading expert in liver disease. How close we are to reliable transplantation of liver from animals? How to overcome challenges to liver xenotransplantation? Liver transplantation from animals: hope and challenges explained. Dr. Anton Titov, MD. Video interview with leading expert in liver diseases Harvard Medical School. Dr. Simon Robson does liver xenotransplantation research for 20 years. Video interview with leading expert in liver diseases about current state of liver transplantation from animals. How close we are to transplant animal organs into humans? There is a progress in farming animal organs for human transplantation. Dr. Simon Robson, MD. Problems are organ rejection and transfer of animal infections. Liver transplantation from animals does not work very well today. Organ rejection happens by complement activation. Modification of pig liver by genetic engineering to prevent rejection is possible. Enzyme CD39 plays important role in transplantation. It removes ATP. Pig liver transplantation is possible as temporary measure until human donor liver is found. Medical second opinion helps to make sure diagnosis of liver failure is correct and complete. Dr. Simon Robson, MD. Medical second opinion in liver failure also helps to choose the best treatment to delay need for transplant. Animal viral infections are Reston ebola type virus and pig cytomegalovirus. They can potentially transmit to human organ recipients. Dr. Anton Titov, MD. Advantages of xenotransplantation are ready source of organs from "farmed animals". Disadvantages are organ rejection and animal infections. Liver transplantation from animals is getting more advanced. Should animal organs be farmed for human transplants? Dr. Simon Robson, MD. Yes, animal organs should be farmed, if transplantation problems can be solved. Xenotransplantation: weighing individual benefit and risks is currently difficult for patients. Because animal donor organs are only a temporary measure in human transplantation. Liver transplantation from animals can help more patients now than before. Animal organs for human transplantation. Pig liver transplant to humans. Dr. Anton Titov, MD. Liver transplantation. Liver is a biochemical laboratory of the body and liver has a remarkable capacity to regenerate. Dr. Simon Robson, MD. But autoimmune and viral hepatitis, fatty liver disease, metabolic syndromes can severely damage the liver. Sometimes only liver transplantation can help the patients. But there are very few liver donors compared with number of patients who need liver transplantation. This brings us to question of liver transplantation from animals (xenotransplantation). You have done major work on liver transplantation from animals. Liver transplantation from animals is one of your major clinical interests. Dr. Anton Titov, MD. What is current state of xenotransplantation technology? What are current advances in liver transplantation? Dr. Simon Robson, MD. Liver specialist, Harvard Medical School. Liver xenotransplantation is a very complex field. We have been looking at transplanting liver from pigs to primates. Liver transplantation model we study is transplantation of genetically modified liver from pigs to baboons. This is a preclinical model of liver transplantation. Dr. Simon Robson, MD. There were transplants from pigs into humans. Pig livers were also used as a perfusion device to correct metabolic problems in acute liver failure. Dr. Titov's note: to clean toxins from human blood by passing it through pig liver. Dr. Anton Titov, MD. Those studies did not show any major benefit to human patients with acute liver failure. There is a problem with the use of swine liver, kidneys, heart for transplantation into humans. Human body very rapidly rejects these pig organs. Organ rejection is mediated by antibodies. This is called complement activation. It is a very heightened immediate and innate immune response. Dr. Simon Robson, MD. We can try to prevent acute rejection of transplanted liver by modification of pig liver. This modification removes major antigens, gal sugar epitopes, from pig liver. These sugar antigens are present on pig liver. Dr. Anton Titov, MD. But humans do not have them. We can delete these antigens from pig liver this is used for liver transplantation. The problem then is excessive blood clot formation on the blood vessels in the donor pig liver. We work to solve this problem by expressing human anticoagulants and antithrombotic molecules. We express these molecules on the surface of pig liver blood vessel lining (endothelium). The focus of my research has been CD39 enzyme. CD39 is an enzyme that removes ATP. ATP activates platelets (and initiates blood clot formation.) We also work on thrombomodulin, this is a human anticoagulant. Pig equivalents of CD39 and thrombomodulin do not work in humans and baboons. what we do is we take the human gene and we human gene into the pig. Dr. Simon Robson, MD. This is similar to human complement activation regulatory genes. Human genes can be expressed in pigs. We express in pigs human clotting regulatory genes to prevent activation of clotting. I am doing this research on liver xenotransplantation for 20 years. I collaborate in liver transplantation work with Dr. David Sachs from Massachusetts General Hospital, with Dr. Peter Cowan and Dr. Anthony d’Apice in Australia. We also work on liver transplantation and pig xenotransplantation with surgeon Dr. David Cooper in Pittsburgh. Dr. Simon Robson, MD. We have achieved dramatic progress in xenotransplantation. First the survival of xenotransplantation organ recipients was only one or two days. This was in a gal antigen knockout model. Dr. Simon Robson, MD. Now survival after xenotransplantation lasts many many weeks. Right now the transplanted pig kidney could survive for 68 days on a life support in a baboon. Heart transplantation from pigs to baboons is not yet life-supporting after 20 or 30 days. Liver is a different issue. Dr. Anton Titov, MD. Liver is so important in generation of clotting factors. We can do genetic engineering of regulatory factors. We can block blood clotting activation in transplanted organ. But with liver xenotransplantation life of recipient is still measured in days. today we can only use liver xenotransplantation as a bridge. In acute liver failure we do not have "dialysis" as we have in acute kidney failure. Patient with acute liver failure can potentially get a pig liver transplant. Dr. Simon Robson, MD. This transplanted pig liver will work for 7 to 10 days in a human patient. We hope that in 7 to 10 days patient with acute liver failure who had pig liver transplantation can partially recover. during this period of time a human cadaveric donor can be found for human to human liver transplantation. For now pig liver transplantation to humans is only a bridge to human donor liver transplantation. Things can change in the future. there have been major advances in liver transplantation field over last 5 to 10 years. Right now we are working on prolonging survival of xenotransplant in recipients. We also work on improving function in transplanted liver. lasting success of pig liver xenotransplantation is still a trip into the future. But we achieved some major advances in liver transplantation. Dr. Anton Titov, MD. today it is the human to human liver transplantation that is clinically significant for prolonged survival. Dr, Simon Robson, MD. Correct. In acute liver failure patients cadaveric liver transplantation can be done. This is liver transplantation from brain-dead donors. Dr. Simon Robson, MD. Living donor liver transplantation can help patients with stable liver disease and chronic liver disease, for example, liver tumors. Dr. Anton Titov, MD. Part of the liver can be resected from a family member or non-relative liver donor. Blood group matching must be done for such liver transplants. Surgeons can resect 50% of liver from a living donor. Within 6 to 8 weeks the remaining liver in the donor will be regenerated to its normal size and normal metabolic capacity. There are very good clinical outcomes in the recipient of liver transplantation from a living human donor. Dr. Simon Robson, MD. Because transplanted liver is not subject to any inflammatory stress. Liver that was stored in cold diseases has inflammation and other problems. Liver from from brain-dead donors also has problems that complicate liver transplantation. patient clinical outcomes are good with living donor liver transplantation. The problem is that normal healthy liver donor is subjected to potentially dangerous surgery in liver transplantation. There is a risk that donor might die during surgery to take part of the liver for transplantation. Dr. Anton Titov, MD. Pig liver transplantation carries a risk of infection and transfer of animal viruses to a human recipient. Dr. Simon Robson, MD. This is a concern in liver transplantation from pig to human. There are pig viruses and bacteria than can cause disease in humans. There is hepatitis E in pigs. Hepatitis E virus can cause disease in humans. Also there are pig retroviruses, for example porcine endogenous retrovirus. This virus can be reactivated when patient is immunosuppressed after liver transplantation. This can cause disease in humans. But infections don't seem to be a major problem in xenotransplantation. Dr. Simon Robson, MD. There is also a pig cytomegalovirus that can be reactivated in human patient after liver transplantation. Pig cytomegalovirus can damage epithelial lining of blood vessels. There are concerns of Ebola virus infection during transplantation. There are other animal viruses than can jump from animals to humans. I find interesting that Reston ebola type virus was found in monkeys from the Philippines. These monkeys were brought to the United States. Fortunately this Ebola type virus did not transmit to humans. But Reston Ebola virus did transmit from infected monkeys to other primates. It caused a lot of problems. Dr. Simon Robson, MD. This Ebola type virus can also transmit to pigs, as was reported from the Philippines, where these monkeys came from. We know that in xenotransplantation we have to be concerned with influenza viruses. Influenza viruses can be transferred between pigs and humans. Pigs and birds are a natural intermediate hosts for influenza viruses. But in xenotransplantation (and liver transplantation between animals and humans) we need to be concerned with other zoonotic infections. Dr. Anton Titov, MD. These are infections that come from animals. Immunosuppression of patients after liver transplantation can predispose patients to these infections. this is an interesting area of transplantation research. There is a lot of discoveries in biology that are important. Dr. Simon Robson, MD. This research has major clinical applications. We hope to find medicines or genetic modifications that prevent xenograft rejection after transplantation of organs from animals. Such discovery will also have important meaning for other human diseases. This discovery will be particularly important for diseases where blood vessels are damages. Liver transplantation from animals: hope and challenges explained. Dr. Anton Titov, MD. Video interview with leading liver transplantation expert. State of liver xenotransplantation.
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