COLUMN ONE : A Second Transplant Revolution : A new generation of anti-rejection chemicals appear more potent and more selective. They may make organ replacement even more routine.
Every week last year, more than 30 livers and hearts were transplanted in the United States in operations that, quite literally, gave the patients months or years of extra life. Just eight years ago, only 62 livers and 103 hearts were transplanted during the entire year.
That sharp increase was a result of the discovery of an anti-rejection drug called cyclosporine, which, by making transplants both safer and more effective, revolutionized the field of transplant surgery to the point where a major organ is transplanted every 40 minutes in the United States.
Today, surgeons are experimenting with a new generation of anti-rejection drugs that may alter the field every bit as much as cyclosporine did. These drugs are more potent than cyclosporine at preventing rejection and, so far at least, seem to have fewer side effects. Some also are cheaper--a not insignificant consideration for drugs that must be taken for the remainder of a person’s life.
But more important, most of the new drugs seem more selective, pinpointing and suppressing only the portion of the immune system that attacks the organ and leaving the rest free to fight off infections.
Dr. Hans Sollinger, a transplant surgeon at the University of Wisconsin in Madison, predicts that the use of transplant drugs will soon bear a strong resemblance to the current situation with antibiotics, where physicians choose from among 20 or more drugs to treat a certain type of infection and a certain type of patient.
“I foresee a time in the future when we will determine the type of rejection, what (immune) cell type is involved, and so forth, open our drawer, and select the proper drug for a given organ and a given type of rejection,” he said.
As a result, transplants will become even more routine than they are now. More people who have a defective organ will be able to receive a replacement and those replacements will last longer than they do now.
On the darker side, however, these developments will increase the demand for donor organs, which are already in short supply. More than 19,000 Americans are on waiting lists for donor hearts, kidneys and other organs, and increased success rates will make the demand even larger.
Attempts at transplants have been recorded as long ago as Egyptian manuscripts written in 2000 BC, but it was not until the 1940s that scientists comprehended how to successfully carry out a transplant. During that period, the late Nobel laureate Sir Peter Brian Medawar of Oxford University demonstrated definitively that transplant failure was caused by the very immune system that protects the body against infections.
Based on Medawar’s work, researchers realized that it was necessary to stop the immune system from attacking an implanted organ as it would a disease-causing bacterium. Unfortunately, the only technique available to suppress the immune system was whole body irradiation, which destroyed all the immune system cells. Several kidney transplants were attempted using this technique. The kidneys survived but the patients did not, succumbing to infections.
The first successful kidney transplant was achieved in 1954 by Harvard surgeon Joseph E. Murray. He used steroids, hormones that suppress the inflammation that is part of the rejection process. Because the steroids did not suppress the immune system effectively, he was forced to use organs from living donors who were closely related to the recipient.
In the late 1960s, chemist George Hitchings of the Burroughs Wellcome Co. synthesized a derivative of a cancer drug that strongly suppressed the immune system. This drug, called azathioprine or Imuran, made transplants practical when it was used in conjunction with steroids. Its development made possible the first heart, lung, liver and pancreas transplants.
But none of these transplant procedures was successful in more than 65% of the patients, and most were much less successful. Furthermore, Imuran’s broad suppression of the immune system left patients susceptible to a variety of infections, as well as to an increased risk of cancer, which is normally kept in check by the immune system.
That situation changed dramatically with the 1970 discovery of cyclosporine in a fungus from southern Norway. Immunologist Jean Borel of the Swiss pharmaceutical firm Sandoz Ltd. showed that it suppressed only a part of the immune system--specifically one type of white blood cell (lymphocyte) called the T helper cell. He speculated that the drug thus could reduce the chance of rejection while leaving most of the immune system intact to fight off infection.
Once surgeons began using cyclosporine in the early 1980s, they never went back to Imuran. At Stanford University, the two-year survival rate for heart transplants jumped from 63% to 83% by 1985. For kidney transplants throughout the United States during the same period, the one-year survival rate leaped from 60% to 80%. But liver transplants showed the most dramatic increase, with one-year survival rates more than doubling, to 70%. Transplant operations flowered as never before.
But cyclosporine had its unfortunate side effects as well. Most critical, it damaged the kidney by lowering its clearance of wastes from the blood--a supreme irony in that the drug had made kidney transplants so successful.
It also did not greatly improve survival rates after the first year: Fewer than 70% of the organs that survived for the first year survived for a second, noted Stanford immunologist Randall C. Morris. In practical terms, that attrition means many patients, perhaps as many as half of all kidney recipients, are coming back for second, third and even fourth organs.
But researchers such as Morris are studying a number of new drugs that they think will change that curve for the better. One of the most thoroughly studied so far is called FK506.
FK506 was discovered in 1984 by researchers from the Fujisawa Pharmaceutical Co. in a soil sample taken only a couple of miles from their laboratory in Tsukuba, Japan. They were using what Morris describes as an “extremely sophisticated”--and still largely secret--system for screening soil and water samples to look for anti-rejection drugs. It is the first such agent that was not found by accident.
The new chemical belongs to a class of bacterial products called macrolides, a family that includes the commonly prescribed antibiotic erythromycin. Fujisawa scientists found that FK506 was 30 times more potent than cyclosporine in suppressing the immune system, which meant that it potentially be could given in much smaller doses to minimize side effects.
But FK506 was almost never used in humans. Immunologist Roy A. Calne of Cambridge University in England found that it was toxic in dogs, and his report in the British journal The Lancet caused many researchers to abandon their studies.
But surgeon Thomas E. Starzl of the University of Pittsburgh Medical Center found that the toxicity varied from species to species. More important, he found that the drug could greatly extend the survival of transplants in animals other than dogs and that it could rescue organs suffering acute rejection episodes.
In February, 1989, 28-year-old Robin Ford was brought into the University Hospital in Pittsburgh because she was undergoing an acute kidney rejection. Starzl decided to use FK506 in conjunction with cyclosporine to try to rescue the organ. The combination proved extremely toxic to Ford, but when Starzl took a gamble and stopped using cyclosporine, FK506 stopped the rejection episode.
Unfortunately, the cyclosporine had already destroyed Ford’s kidney, but she received FK506 along with a second donor organ and is back at work for the first time in two years. Most important, Starzl had seen the potential of the drug.
Starzl has used the drug in more than 300 liver and kidney transplant patients with uniformly good results. Interestingly, Morris said, the drug not only halts rejection episodes, it also stimulates regrowth and repair of damaged liver cells. “No other drug does that,” Morris said.
Starzl said that most patients who receive the drug leave the hospital within two weeks after a liver transplant, about half the recuperation time required with cyclosporine. They also have fewer rejection episodes, infections and, so far at least, side effects.
Because of the improved recuperation time, Starzl predicted that the cost of liver transplants will be reduced by at least one-third from the current level of about $200,000, and that cost reductions also will be achieved with other types of transplants.
Clinical trials of the drug at other medical centers are expected to begin shortly.
A variety of other drugs that promise to improve on FK506 are being studied at Stanford and elsewhere.
To speed up research on the drugs, Morris has developed an innovative technique: He takes small pieces of heart tissue from one strain of mouse and places them between the cartilage and skin in the ears of mice from a different strain. Blood vessels grow into the heart tissue and within four to six days, the muscle tissue begins beating, although it is not pumping blood.
“If we don’t treat the recipient, it will be rejected in 10 days,” he said. “We can treat it with new drugs to see how long the hearts beat. This has really speeded up the process of drug discovery and development.” If drugs appear promising, they are tested in rats and monkeys before trials in humans. “When we test them head-to-head like this, we can make clear distinctions among them and see what the role of each will be,” he said.
One new drug that Morris considers promising is rapamycin, a close relative of FK506 that was discovered in the 1970s by researchers from Ayerst Laboratories in Canada who were looking for antibiotics to fight yeast infections.
Rapamycin was a good antibiotic, Morris said, but it also interfered with the immune system, so it was shelved. But it was that very property--plus the fact that it has a molecular structure much like that of FK506--that prompted Morris to evaluate it as an anti-rejection drug.
“I didn’t expect it to be much different from FK506,” Morris said. “I was very, very surprised because in rats it is very potent”--about 60 times as potent as cyclosporine and twice as potent as FK506. “It’s the most potent drug we’ve ever seen.” Morris hopes to begin testing rapamycin in primates this year.
Morris has high hopes for another drug called RS-61443 because it operates by a completely different mechanism than FK506 and other macrolides and thus may be able to intervene at a different stage of rejection.
Morris has tested RS-61443 in all three animal systems--mice, rats and monkeys--and found that it could prevent rejection and reverse advanced rejection. It is particularly promising, said Wisconsin’s Sollinger, who has also tested it in dogs, because it combats chronic rejection, which none of the other available drugs does.
Sollinger used the drug--which is routinely used to treat the skin disease psoriasis--for the first time in a human transplant patient in April, and he and researchers at the University of Alabama plan to study it in more kidney transplant patients. Morris said that the Stanford team plans to test RS-61443 in heart transplant patients, perhaps as early as this summer.
Two other drugs deserve mention. One is deoxyspergualin, a bacterial product that “is more impressive than FK506 in some species, particularly primates,” said surgeon Robert Corry of the University of Iowa Medical Center.
Deoxyspergualin already has been used successfully for a small number of kidney transplants in Japan and kidney and pancreas transplants in Europe. Corry is head of a group of U.S. investigators who plan to begin testing the drug in humans this summer. The test group will consist of patients receiving a second kidney.
“We’ll be dealing with a population for which there is a 60% success rate rather than 90%” as is the case with first kidney transplants, he said. “If we have a success there, it will be more clear-cut than it would be with patients who are already doing pretty well.”
The other drug that is attracting interest is not new, but it is one that was largely discredited 25 years ago. Thalidomide was developed as a tranquilizer and a sleeping aid, but those uses were abandoned after it caused unusually severe limb deformities in almost 12,000 European children whose mothers took the drug while they were pregnant; the drug was never approved for use in the United States.
Now, researchers at the Johns Hopkins School of Medicine in Baltimore are finding that it is useful in treating recipients of bone marrow transplants, which are used for the treatment of certain types of cancer, such as chronic myelogenous leukemia.
These transplants are unusual because the transplanted organ--bone marrow--is the source of lymphocytes and thus part of the immune system. When the transplant goes bad, the body does not reject the transplant: The transplanted organ rejects the body. This graft-versus-host disease, which affects nearly half of the 2,000 cancer patients receiving bone marrow transplants each year, causes severe damage to the recipient’s tissues, even death.
Thalidomide, said oncologist Georgia B. Vogelsang of Hopkins, is the only drug that has been shown to reverse graft-versus-host disease in animals once it has started.
Vogelsang and her colleagues have treated about 100 patients with thalidomide, and were successful in reversing graft-versus-host disease in about 60 of them. In half the other cases, she noted, the drug was not absorbed by the patient’s body and thus never had a chance to function.
The only significant side effects she has observed, Vogelsang said, are sleepiness and mild constipation. Birth defects are not a problem because the radiation used to destroy a patient’s own bone marrow before the transplant sterilizes the recipient.
Researchers still do not know completely what to expect with all these new drugs. “We’re still in our infancy with all these things,” Corry said. But they all hold out high hope for the future.
“Our main message to people who will need transplants is to have hope and patience because there are some nice therapeutics out there,” Morris said. “There really is a light at the end of the tunnel.”
