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RESIDENT ALIEN:
To T cells and antibodies, a new organ is anathema // yet with cellular camouflage // a foreign body can hide in plain sight.

The Transplant Trick

By Rachael Moeller Gorman // Illustrations by Richard Wilkinson // Spring 2009
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chimerism, organ transplants

Transplant surgery has come a long way since 1954, when Joseph E. Murray, at what was then called the Peter Bent Brigham Hospital in Boston, removed a kidney from one identical twin and implanted it in the abdomen of the other. The recipient survived eight years, and in the decades since then such medical miracles have become almost routine, with hands and even faces entering the realm of remarkable possibilities. In a recent innovation, surgeons at Johns Hopkins University managed to remove a healthy kidney for an aunt-to-niece transplant through the donor’s vagina, avoiding long abdominal scars.

Yet despite such progress, twenty-first-century transplant patients still face the problem that has plagued recipients from the start: Sooner or later their bodies are likely to reject the donated organ. To prevent the immune system from attacking a new heart or liver just as it would a parasite, virus or bacteria, patients take powerful immunosuppressive drugs. But that daily regimen, by tamping down immunity, can let infections run rampant and increase the risk of many cancers, which may take hold when defenses are down. There are also unpleasant side effects—warts, excessive body hair—and the drugs can lead to reduced renal function, diabetes, hypertension, neurotoxicity and other chronic conditions. And even then, organ rejection can occur. The immune system’s T cells trigger inflammation while antibodies attack the organ until it’s damaged beyond repair. Ten years after surgery, only about half of transplanted organs still function.

One way to sidestep the need for immunosuppression and improve the success rate would be to persuade the body that the new tissue really isn’t foreign. That can sometimes be accomplished through a mechanism called chimerism, in which cells from the organ donor fool the recipient’s body into 
believing the transplanted tissue is its own and thus poses no danger. That possibility has intrigued scientists for decades, dating at least to the early 1950s, when British biologist Peter Medawar showed that adult cattle twins that became chimeric in utero because of interconnected blood vessels could receive skin grafts from each other without rejection.

Medawar’s research led to further studies, mostly in mice, of ways to induce chimerism. Certain complications make it difficult to attempt this method in humans, however, and relatively few treatments have been tried. But in early 2008, a team of scientists and clinicians led by David H. Sachs, director of the Transplantation Biology Research Center at the Massachusetts General Hospital, and A. Benedict Cosimi, chief of the MGH’s transplant unit, published the results of a clinical trial in which they were able to take four transplant recipients off immunosuppressant drugs—a remarkable achievement.

According to their report, published in The New England Journal of Medicine, the patients remain healthy and free from kidney disease and the tribulations of immunosuppressant therapy. The MGH team gave the patients bone marrow as well as kidneys from donors, and the recipients became part “other”—their bodies didn’t reject the organs because they didn’t consider the transplanted kidneys foreign. Scientists elsewhere are also trying to use chimerism to transplant a variety of tissues and have succeeded in taking some patients off immunosuppressants. Others, though, don’t consider chimerism a key to drug-free transplantation: They think other mechanisms are at play and need to be harnessed instead. Still, the MGH team’s results, though limited, are too intriguing to ignore.

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Hard to Get (And Keep)

After transplants, organ recipients face handsful of immune-suppressing drugs per day and the constant threat of rejection.

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hed-dossier

1. 
“The Use of Skin Grafting to Distinguish Between Monozygotic and Dizygotic Twins in Cattle,” by D. Anderson et al., Heredity, 1951, and “Tolerance to Homografts, Twin Diagnosis, and the Freemartin Condition in Cattle,” by R. E. Billingham et al., Heredity, 1952. Two papers highlight Peter Medawar’s early exploration of chimerism, a foundation for the MGH team’s ability to remove patients from immunosuppressive drugs nearly 60 years later.

2. 
“HLA-Mismatched Renal Transplantation Without Maintenance Immunosuppression,” by Tatsuo Kawai et al., The New England Journal of Medicine, Jan. 24, 2008. The MGH team uses David Sachs’s strategy for taking human kidney recipients off all immunosuppressive drugs.

3. “Immunosuppressive Therapy and Tolerance of Organ Allografts,” by Thomas E. Starzl, The New England Journal of Medicine, Jan. 24, 2008. A transplant pioneer outlines the downsides of Sachs’s new procedure.

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