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A report on Baboon-to-Human Liver Transplantation

The often-tragic lack of donated human organs has led to serious research into xenotransplantation¾ transplanting an organ from one species of animal into another. If xenotransplantation is performed successfully from an animal such as a pig or baboon to a person, there is a potential to save hundreds or even thousands of lives each year.

The following article by Dr. Ignazio Marino of the University of Pittsburgh Medical Center (UPMC) in Pittsburgh, Pennsylvania discusses the landmark xenotransplant procedures he and other transplant surgeons at UPMC conducted in 1992 and 1993. This exciting research spurred interest around the world in xenotransplantation.

BABOON-TO-HUMAN LIVER TRANSPLANTATION
A POSSIBLE SOLUTION TO THE ORGAN SHORTAGE?

<p>By Ignazio R. Marion, MD, FACS, Associate Professor of Surgery at the University of Pittsburgh Center, Associate Director of the National Livewr Transplant Center of the Vetrerans Affairs Medical Center of Pittsburgh

The organ shortage has become a real crisis. This is particularly important when considering the number of patients awaiting liver transplant because, unlike patients awaiting other organs, patients with terminal liver illnesses cannot benefit from any type of artificial back-up system. This clearly justifies the renewed interest in xenotransplantation which has occurred in the last decade.

In May, 1992 a study performed in Pittsburgh using a hamster-to-rat xenotransplant model clearly showed that indefinite survival was routinely achievable if tacrolimus was combined with either of two ‘antiproliferative’ drugs: mycophenolate mofetil or brequinar sodium, and that the use of cyclophosphamide allowed similar consistent chronic survival. On this premise, the Pittsburgh Transplantation Institute notified the National Institutes of Health, the Food and Drug Administration, and the Department of Health of its intention to proceed with the baboon-to-human liver xenotransplant project and, after making several modifications to the initial protocol, the first xenotransplant was performed on June 28, 1992, and the second on January 10, 1993.

The immunosuppressive regimen was comprised of four drugs: cyclophosphamide, tacrolimus, steroids and prostaglandin. The protocol for this human trial allowed the baboon-to-human liver transplant for the treatment of end-stage chronic active hepatitis B virus. This decision was made because recurrence of infection after liver transplant for hepatitis B virus is high, and the baboon liver is thought to be resistant to the development of chronic active hepatitis B. The first patient, already able to feed himself at five days post-transplant, lived for 70 days with a relatively normal quality of life. The second patient, who was much older, unfortunately never regained a level of consciousness sufficient to allow him to be weaned off the mechanical ventilator, and survived for only 26 days. Considerable liver regeneration was noted in both cases, with a significant increase in the size of the baboon livers, which in a couple of weeks had grown to the size of a normal adult human liver. Cellular rejection was not a problem with either patientÑtherefore, the antirejection cocktail used was sufficient to protect the baboon liver from this type of immunological injury. The first patient’s death was due to a brain hemorrhage, caused by aspergillosis, which is an opportunistic infection. The second patient’s death was due to bacterial sepsis.

During the operation, the second patient was also given an infusion of bone marrow cells from the donor baboon. This was aimed at increasing the natural tolerance induced by the liver transplant. In fact, these cells participate in two-way cell traffic, which gives rise to microchimerism, or compatibility of the cells between the recipient and donor organ. The autopsy on the first patient confirmed these expectations, since baboon DNA was found in the patient’s heart, kidneys, lungs and lymph nodes. All blood samples taken from the second patient during the post-operative course also showed the presence of the baboon DNA.

One of the most disquieting findings in our baboon-to-human liver transplant experiences was that the transplanted grafts did not fail due to traditional rejection, but did not function well, either. We suspect that these livers were acutely damaged by a form of rejection related to a protein named ‘complement,’ which can damage the animal organ, even if there were no antibodies present. Recently, the introduction of the concept of systemic chimerism, or the compatibility of the cellular make-up of the transplanted organ to that of the recipient’s own system, has heightened interest in designing strategies aimed to alter the cell composition of the graft. The creation of a transgenic pig (developed by the injection of human DNA into the fertilized swine egg), to be utilized as a source of organs for clinical xenotransplants, has already been started in a few laboratories. The scientists working on this project have embarked on a program to produce transgenic pigs, whose human DNA regulates some of the protein involved in rejection. However, only one of the many types of rejection can be overcome by this strategy; therefore, it is difficult to hope that a complete control of rejection will be achieved by this method alone.

One other extremely fascinating possibility is the production of chimeric organs. Human-to-baboon bone marrow transplantation has already been performed at the Thomas E. Starzl Transplantation Institute laboratories. In this experiment, two baboons were given unaltered human bone marrow cells, without any subsequent treatment. Human DNA was found widely distributed in the tissues of both animals when sacrificed 18 months later.

As recently stated by Dr. Thomas Starzl: ÒIt remains to be seen if incomplete or even full chimerism will change the image of baboon organs enough to make them viewed as allografts (organ from the same species) by humans.’

The controversy surrounding xenotransplantation has become heated because of concerns regarding potential risks of infectious diseases from animals to humans, and because of abuse concerns from animal rights activists. But there remain two important facts: thousands of people die while awaiting organ transplants each year because of the shortage of available organs; and animal-to-human transplant provides the possibility of an abundance of organs to save human lives. With those important facts in mind, cautious yet ground-breaking research is continuing in xenotransplantation. Perhaps someday xenotransplantation will become as successful and far-reaching as transplantation is today.

With thousands of people on the waiting list and precious few organs to fill the need, medical researchers across the country are exploring the area of artificial organ technology. Partial artificial hearts, called left-ventricular assist devices (LVADs) have been implanted in more than 700 patients while awaiting heart transplants. Bioartificial livers are being used experimentally at Cedars-Sinai Medical Center in Los Angeles, California. Artificial lungs are being studied at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania. The Texas Heart Institute at St. Luke’s Episcopal Hospital in Houston, Texas is investigating three different implantable heart devices. The list of medical centers working on the development of artificial organs goes on, with each study holding potential for success¾ and the possibility of saved lives in the future.