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Toward a New Source of Organs

A natural phenomenon is lighting the path to minimizing organ rejection and, one day, using animals as donors.

By Charles Slack // The MGH Research Issue 2011
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Sam Kaplan for Proto

When cows get pregnant with fraternal twins, a quirk of nature sometimes results. During gestation the fetuses, attached to the same placenta, exchange blood cells as their bodies develop. Each calf is born with a mixture of its own physical characteristics, including blood type, and the twin’s.

To cattle breeders, the phenomenon (almost exclusive to the species and impossible to prevent) is a costly annoyance, because 9 out of 10 females born with a male twin turn out to be sterile. Yet these unusual calves helped the science of organ transplantation leap forward in the early 1950s, when the British researcher Peter Medawar demonstrated that skin could be grafted from one calf twin to the other without any sign of the rejection that inevitably occurs in other transplants.

Later research would show that the twin calf fetuses exchange blood stem cells (known as hematopoietic stem cells), the source of the immune cells that protect the body from invaders. Because the calf receiving a graft already has immune cells from its twin, the recipient’s immune system regards the grafted skin as its own and doesn’t attack it.

David Sachs, director of the Transplantation Biology Research Center at Massachusetts General Hospital, speaks of this phenomenon in cattle with the same excitement he felt as a second-year student at Harvard Medical School in 1965, when he first heard of it. By proving that one body could accommodate two separate immune systems—an example of chimerism, named for a multispecies creature from Greek mythology—nature itself seemed to be lighting a path to solve the two most vexing problems that have beset organ transplantation ever since Boston surgeon Joseph E. Murray of the Peter Bent Brigham Hospital performed the first successful kidney transplant in 1954: rejection and scarcity of organs. Sachs has spent his career trying to follow nature’s example in overcoming those twin challenges.

Organ rejection results from the body’s defense mechanisms. T cells, produced by stem cells in the bone marrow, quickly detect and destroy invaders they don’t recognize. Yet, while essential in fighting disease, T cells have no way of knowing whether an invader is a bacterium, a virus or a lifesaving organ transplant.

To minimize the chance of rejection, doctors look for organs that are a good genetic match—it’s particularly important to have similar human leukocyte antigens, or HLAs, proteins on the surface of the body’s cells. And powerful immunosuppressant drugs aid in limiting T cells’ ability to function. Yet even under the best conditions, organ recipients face a 5% to 7% chance of rejection each year, which means that in a decade’s time, at least half of all transplants end in failure. Moreover, the drugs must be taken for life and can cause serious side effects, ranging from painful, debilitating warts to infections and even cancer.

To replicate the chimerism of calf twins, Sachs and other researchers injected bone marrow from one mouse into the bloodstream of another. The recipient could then accept a skin graft from the donor with no sign of the usual rejection. Though complexities mount as one moves up the species chain toward humans, Tatsuo Kawai, an MGH transplant surgeon who works with Sachs, and A. Benedict Cosimi, chief of the MGH Transplantation Unit at the time, successfully performed the procedure on monkeys starting in the early 1990s.

By 2002 the MGH transplant team was ready to try the procedure on human recipients of mismatched kidneys. Jennifer Searl, a 22-year-old suffering from kidney failure since the age of 12, had already rejected a kidney that was not a perfect match. Now, from her mother, she got a kidney that was not well matched. But this time, Searl had the benefit of an infusion of her mother’s bone marrow that used a protocol similar to the one Sachs had developed in mice, and within nine months she was able to go off all her immunosuppressants. Nine years later, still without drugs, the kidney hasn’t been rejected.

The procedure that Searl underwent has significant risks and difficulties beyond the customary rigors of transplant surgery. Chimerism patients have to receive chemotherapy to kill off their adult T cells and make way for the donor cells, and after the transplant they must be observed for several weeks in the hospital. Yet during the past decade, the MGH team has used chimerism to transplant kidneys into 10 additional patients, seven of whom continue to have functioning kidneys and don’t require immunosuppressants. (The other three suffered rejection and still need the drugs.)

MGH doctors are looking for ways to make the chimerism transplant regimen easier on patients, a prerequisite for more routine use. But even that would do little to address the problem of having far too few organs to meet demand. Every day in the United States, an estimated 18 Americans die while awaiting human hearts, lungs, livers or kidneys. That’s why, for Sachs, the ultimate goal of chimerism has been to induce tolerance across species.

Though early research in xenotransplantation—the introduction of animal tissues and organs into humans—was aimed at using chimpanzee kidneys for patients with advanced renal failure, Sachs has long focused on the possibility of using pigs. They’re easily bred and kept, and a breed of miniature swine that Sachs works with grows only to around 200 pounds and has organs about the same size as those of humans. What’s more, the routine slaughter of pigs for meat means their use as organ donors may be more ethically acceptable than sacrificing nonhuman primates.

The problem that remains, of course, is to get the human body to accept a nonhuman organ, and immunosuppressant drugs don’t help adequately. Pigs, like most other mammals, produce a sugar called alpha-1,3-galactose (known as Gal) on the surface of their cells. Primates, including humans, don’t have the sugar, and in test transplants from pig to baboon, antibodies in the recipients detected Gal with lightning speed and rejected organs almost immediately—sometimes killing the organ even before the transplant procedure was complete.

Scientists at BioTransplant Inc. and the University of Missouri, using cells from pigs bred by Sachs, replaced the Gal gene with a similar but nonfunctioning gene and subsequently created Gal-free pigs. In a major leap forward for xenotransplantation, baboons with kidneys from these pigs have survived for as long as 83 days.

But other challenges remain. Pig bone marrow cells introduced into a primate are destroyed by the recipient’s liver before they have a chance to create the chimeric effect. In this case, it’s not T cells that are the problem but rather a liver function that cleanses blood by recycling red blood cells after they have lived their useful span of about 120 days. The way around this roadblock could involve a molecule on the red blood cells’ surface, known as CD47 (present in humans and other primates, but not in pigs), which signals the liver not to destroy the cells prematurely. Now researchers are experimenting with genetically introducing CD47 to swine marrow cells to win the few weeks needed to induce chimerism.

Meanwhile, though successful long-term pig-to-human transplants are still several years off, Cosimi thinks there might be an interim step in which pig livers could become reliable enough to last a few months in patients who would otherwise die awaiting a human donor. And Sachs, who as a dauntless medical student in 1965 believed he would quickly solve the chimerism riddle and move on to other challenges, will instead go on with the work that has continued to fascinate him for more than 45 years. Though the ultimate goal has eluded him so far, the steps he’s taken along the way in understanding immune tolerance have been no less than vital.

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That’s Some Pig

xenotransplantation

Sugar-free and engineered for tolerance, hogs may one day fill a need for transplant organs.

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