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UPMC surgeons perform second baboon to human liver transplant

PITTSBURGH, Jan. 11, 1993--Surgeons from the University of Pittsburgh Medical Center (UPMC) announced they performed the world's second baboon-to-human liver transplant on a 62-year-old man dying from hepatitis B, for whom there was not the option of a human-to-human transplant. The 13-hour operation began Jan. 10, 1993 at 11:15 a.m. and ended at 12:35 a.m. Jan. 11. Some modifications in the procedure and treatment were made by the transplant team based on recent research advances and knowledge gained from its first attempt on a 35-year-old man who was transplanted on June 28, 1992.

According to a report published in the British medical journal, The Lancet, the first patient died of a brain hemorrhage caused by a fungus infection 71 days after his transplant. Obstruction in the liver's bile ducts by sludge, a semi-solid substance comprised of cholesterol and bile pigments, and complications of immunosuppression with an otherwise effective combination of drugs may have also contributed to his death, the Pitt team reported. 

Based on these results, surgeons are changing the timing of doses of the immunosuppressant drugs used, in particular, cyclophosphamide, so that the risk of infection is reduced. The combination of drugs remains the same: FK506, cyclophosphamide, prostaglandin, and prednisone. 

To better detect sludge formation, surgeons John Fung, M.D., Ph.D.; Satoru Todo, M.D.; and Andreas Tzakis, M.D., inserted a tube into the baboon liver's primary duct and guided it outside the patient's abdomen during the operation. The tube allows the ducts to be flushed in order to prevent or clear any formation of sludge and also permits more conclusive diagnostic studies to be performed during the patient's recovery.

As a measure to promote acceptance of the transplanted liver, surgeons infused a suspension of white blood cells from the baboon's bone marrow into a vein of the recipient. The procedure took place as follows: while the transplant surgery was underway, a separate team of surgeons was isolating and purifying the cells from the donor's bone marrow. Ten hours later, as the new liver was being sewn in, the cell transplant team began infusing a small quantity of the cell suspension into a vein in the recipient's neck. The infusion of cells began at 9:20 p.m. and took approximately one hour.

"While the combination of four drugs we used in the first case was shown to be effective in controlling rejection, we believe the bone marrow infusion in the second patient will be an extra boost to produce chimerism and enhance acceptance of the new organ," said Thomas E. Starzl, M.D., Ph.D., director of Pitt's Transplantation Institute. "The transfusion contains the immune system cells we believe are important for chimerism," he added.

Chimerism is the cellular environment consisting of both recipient and donor cells, which the Pitt team believes is necessary for acceptance of transplanted organs. It has recently been identified in successful animal and human transplant recipients by the Pitt researchers and was also evident in the first baboon liver recipient. Baboon cells were found in the patient's blood during his life, and at autopsy, cells were found in his heart, lungs, kidneys, and lymph nodes. 

"The introduction of the donor's immune system cells to the recipient's own immune system promotes a state of acceptance. Immune system cells from the donor should protect the transplanted liver by preventing the recipient's immune system cells from launching an attack. In addition to their immunosuppressant properties, we believe the drugs also act as facilitators of communication between the donor and recipient immune system cells," explained Dr. Fung, chief of transplantation and an associate professor of surgery.

Injecting bone marrow cells promotes a cellular environment that reduces the chances of rejection even more than is possible with drugs alone.

According to the surgeons' Lancet report, the four drugs, in the absence of bone marrow cells, effectively prevented antibody-mediated rejection, the primary obstacle to successful cross-species transplantation. Antibody-mediated, or humoral, rejection occurs when the immune system's B cells cause the production of antibodies that attack the donor organ. Augmented with standard steroid treatment, the drugs also controlled a minor episode of cellular rejection that occurred early in the first patient's clinical course. Rejection of this kind involves T cells.

FK506, a drug manufactured by Fujisawa Pharmaceutical Co., Ltd., of Japan and developed at Pitt to combat rejection, works to suppress the recipient's T cells from attacking the donor organ. Cyclophosphamide, a Bristol-Myers Squibb drug developed to treat cancer, was shown to hold promise for transplant recipients by Dr. Starzl more that 20 years ago. Commercially known as Cytoxan, cyclophosphamide prevents B cells from proliferating, a process which occurs in the presence of an antigen -- a foreign substance -- and results in the production of antibodies that help destroy the foreign substance. It is cyclophosphamide that the Pitt team is modifying the way it is administered in the second baboon liver recipient.

The two other drugs that make up the four-drug cocktail are prednisone, a steroid hormone that affects those cells which help to recognize and process antigens, and prostaglandin, which serves to subdue the chain reaction of events likely to occur in the immune system response.

Pitt's Institutional Review Board gave its approval to the transplant team to proceed with four baboon-to-human liver transplants, contingent on case-by-case review, for patients with chronic, active hepatitis B. Hepatitis B is considered by many members of the transplant community to be a contraindication for human-to-human liver transplantation because of the great likelihood the disease will recur in the newly transplanted liver. 

"Baboons do not appear to be able to be infected with hepatitis B, so as sources for organs, they may offer a solution for these patients," said Dr. Starzl before the first transplant.

Surgeons were encouraged that there was no evidence of the viral infection in the first recipient's liver when examined at autopsy, but said he did not live long enough to state conclusively that a baboon's liver, when transplanted, is indeed resistant to hepatitis B.

The baboon was also selected as a source because it is not an endangered species and can be bred safely and easily in captivity. 

Cross-species transplantation, or xenotransplantation, has long been considered an answer to the critical shortage of available human donor organs. While patient waiting lists have become longer, the inadequate supply of donor organs persists. Nationwide, at least one patient dies each day while waiting for a liver transplant, and this figure has increased each year.

Although early attempts at xenotransplantation date back as far as 1905, new understanding of the immune system and subsequent new drugs created the scientific climate for several attempts in the 1960s, at a time when dialysis treatment and cadaver organs were not widely available. In 1963 and 1964, Keith Reemtsma, M.D., performed chimpanzee-to-human kidney transplants in 12 adults at Tulane University. One recipient lived with the kidney for nine months without evidence of rejection before dying of an infection. Soon after this series, other surgeons made unsuccessful attempts to transplant a chimpanzee heart and kidney, and Dr. Starzl performed kidney transplants in six adults using baboon donors. Between 1969 and 1974, Dr. Starzl provided chimpanzee livers to three children, one of whom lived 14 days before succumbing to sepsis, a widespread infection. Surgeons at Loma Linda University had available the anti-rejection drug cyclosporine when Baby Fae received a baboon heart in 1984. The infant died of rejection 20 days after surgery. Between 1963 and 1984, 28 clinical procedures involving solid organs from animal donors were performed in the United States and South Africa.

In addition to the world's first baboon liver transplant last year, a woman at the Cedars-Sinai Medical Center in Los Angeles lived with both her own liver and a pig's liver for 32 hours while awaiting a suitable human donor.

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