WTC: New Life for Xenografts

BOSTON, July 26 -- The major immunologic barriers to xenotransplantation of solid organs are beginning to fall, researchers reported here.

It may be only a matter of years rather than decades before the first formal clinical trials of inter-species organ transplantation are underway, according to David H. Sachs, M.D., and Megan Sykes, M.D. of Harvard Medical School and the Massachusetts General Hospital here.

The trials are likely to begin as bridges until a human organ becomes available, but later as potential replacements for failed human hearts, livers, kidneys, and other organs, Dr. Sachs said at the World Transplant Congress.

The need for xenotransplantation is clear, said Dr. Sachs, who is director of the transplantation biology research center at Mass General.

"It's paradoxical: the field of transplantation itself has done so well over the past few decades that we're now faced by a major limitation brought on by the success of allogeneic transplantation," he said. "We just don't have enough organs. There are thousands of people dying each year waiting on the waiting list for organs, and many others who don't even get on the waiting list."

The field of xenotransplantation research has come a long way since 1984, when surgeons at the Loma Linda Medical Center in California desperately tried to prolong the life of a newborn girl born with severe hypoplastic left heart syndrome by implanting in her a baboon heart. A baboon heart was chosen because of its size and because of the genetic similarity between humans and baboons.

The child, known as Baby Fae, lived for just 20 days after the surgery. The problem, then as now, was immunologic.

One of the most important research advances that has brought xenotransplantation closer to clinical application is the development of pigs that have been genetically engineered to remove expression of galactosyl alpha(1-3) galactose, known simply as "Gal."

"This is the most powerful antigen that causes rejection when you go across a difference species difference like pig to human," Dr. Sachs said.

Nearly all research centers are focusing efforts on pigs, which don't come with the ethical baggage that monkeys and apes do, and pigs are also in no danger of becoming extinct, in contrast with many of our closest primate relatives.

Because the gene for expression of Gal evolved out of primates millions of years ago, humans have developed antibodies to it, and previous attempts to implant animal organs in humans have lead to episodes of hyperacute rejection, in which organs fail within a matter of hours or days.

"Over the last three years, this problem appears to have been eliminated," Dr. Sachs said. "Before then we were always absorbing the antibodies, inhibiting the antibodies, absorbing the complement -- nothing really worked, but now with genetic engineering of the pig to prevent the expression of Gal, I think we've made a major advance."

Dr. Sykes said that although many people expect that beta islet cell transplants will be the first practical application of xenotransplantation techniques, that is not certain. "Islet cells require fairly intensive immunosuppressants, and islet transplants obviously are not immediately life saving, and you have a form of therapy for diabetes -- insulin -- that is life-saving," she said.

Dr. Sykes added that immune tolerization -- teaching the immune system to accept foreign tissue without a lot of fuss -- is likely to be necessary if porcine islet cell transplants are to succeed.

One such technique may be controlled mixed chimerism, in which the donor and recipients cells mingle until the immune system learns to adopt the foreign cells as its own.

Dr. Sykes, Dr. Sachs, and colleagues at Mass General's transplantation unit reported results of a study showing that a method for inducing tolerance of HLA-mismatched renal allografts through mixed chimerism allowed three of five patients to discontinue immunosuppressants, and a fourth patient to be have immunosuppressants titrated downward to low levels.

"This can be extended to xenografts," Dr. Sachs said. "We've already done it for allografts, and if it can be extended to xenografts, that would be a major advance."