Transplant Surgery - A Delicate Balance

Transplant Surgery - A Delicate Balance
By Joan Raymond | Newsweek Web Exclusive
Feb 8, 2009 - 12:51:34 PM

(HealthNewsDigest.com) - In an incredibly complex 22-hour procedure, the Cleveland Clinic's microsurgical-research team performed the United States' first almost-total face transplant last December. The procedure gave a disfigured woman a chance at a normal life, a life that began today when she left the hospital. It's also another demonstration of the astonishing progress the medical community has made in transplant surgery. For most of us, the awe-inspiring story ends there. But for a transplant patient, finding a donor and then surviving surgery is only half the battle. Next comes a lifelong fight to keep the human body from doing what it is exquisitely designed to do: reject foreign bodies and tissue.

And in this arena, researchers are still struggling with a complex problem. The immunosuppressive drugs that patients need to take to prevent organ rejection are toxic, and the side effects can be debilitating or even deadly in the long term. Medication dosage or quantity can be reduced to limit toxicity, but that also increases the risk of rejection. Alternately, the immune system may be suppressed too much, and infection may overwhelm the body. Finding the right balance is a delicate, sometimes impossible task.

The balancing act can be rough on patients. Laura Ellsworth, 33, of Vancouver, Wash., underwent a living donor kidney transplant 10 years ago with a kidney donated by her father. She takes 17 different pills every day, a mixture of immunosuppressive drugs and medications to control her blood pressure. The regimen increases her risk for heart disease, infection, skin cancer and osteoporosis. She visits a dermatologist regularly for skin-cancer checks, and even though she's only in her early 30s, she has undergone several bone scans to check for osteopenia, a precursor of osteoporosis.

Despite the challenges for patients, it's clear that transplant medicine is making advances. Doctors are able to keep transplanted organs functioning for longer lengths of time, and most of the approximately 250,000 people living with transplants in the United States, like Ellsworth, are living full, productive lives. Still, a majority of transplanted organs do eventually fail. And patients have to be vigilant about protecting their fragile immune systems to give themselves a fighting chance.

One sign of hope lies in a promising new experimental procedure developed by Dr. David Sachs, head of the Transplant Biology Research Center at Massachusetts General Hospital and a professor of surgery at Harvard Medical School. In a small trial, Sachs was able to achieve immune-system tolerance in several transplant patients completely without using immunosuppressive drugs.

Though the immune system is elegant—distinguishing between the organs, blood, tissues and cells that are part of the "self" and outside invaders such as splinters, dust or germs—it isn't perfect. Splinters become infected, dust can trigger allergies and germs can get through immune-system defenses. When it comes to organ transplants, the challenge is that the immune system is not making a mistake. Except in the case of identical twins, a transplanted organ is "non-self," and the immune response to the transplanted organ is all-out war. "What the immune system wants to do is destroy that organ," says Dr. Sang-Mo Kang, associate professor of surgery at the University of California San Francisco and surgical director of the Intestinal Rehabilitation and Transplantation Program. "Evolution or nature never envisioned the transplant. And therefore, the immune response is absolutely incredible."

Jennifer Searl, one of Sachs's patients, knows all about that powerful immune-system response, and how devastating it can be when the immunosuppressive drugs aren't able to fight it properly. She had her first kidney transplant when she was 13 years old (as in Ellsworth's case, a kidney donated by her father). Her 10-year stint on the immunosuppressive drugs she needed to keep that kidney functioning was horrific. She was taking 20 pills a day and developed cataracts, high-blood pressure, osteopenia, and painful viral warts on the sole of her right foot.

"It was absolutely the worst time of my life," says Searl, now 29 and a research librarian in Peabody, Mass. "It was like trading one disease, my kidney disease, for a bunch of other horrible problems caused by these drugs. I hated them."

Her immune system eventually overcame the drugs and her body rejected the kidney. Things looked bleak, but then she met Sachs. Thanks to the Massachusetts General doctor, Searl is thought to be the first person in the world in whom immune-system tolerance was achieved in a non-matched kidney transplant (where the donor organ is different from the recipient's tissue type, as is the case in all transplants except those involving identical twins). She has been off immunosuppressive medications for more than six years, an extraordinary accomplishment.

Although there has been some success in weaning patients off immunosuppressive drugs when a donor is closely matched, transplant recipients in Sachs's protocol received kidneys that were mismatched, like Searl's. These types of transplants are the most common and, unfortunately, are the most likely to fail, even with an onslaught of anti-rejection drugs: 10 percent will fail within one year, 30 percent within by five years and 45 percent within 10 years.

Sachs's procedure involves partially destroying the patient's bone marrow before the transplant to reduce the number of cells involved in organ rejection. Searl went through the protocol in 2002 with a kidney donated by her mother. During transplant surgery, her mother's bone marrow was injected into one of Searl's blood vessels, in the hope that Searl's immune system would achieve "mixed chimerism," essentially a state in which a patient's immune system takes on some of the characteristics of the donor's.

"The results were outstanding," Sachs says of the procedure, which was successful in 4 of the 5 patients he has used the protocol on. (The results of the trial were published in The New England Journal of Medicine in January 2008.) "We were ecstatic, but everyone has to realize this is just one step." The next step, according to Sachs, is to see if the regimen works in a larger group of patients. "We need much more patient experience, but the ultimate goal is to help transplant patients live longer and live more normal lives," he says. If all goes well, Sachs hopes the protocol will eventually be extended to all transplanted organs.

Dr. Maria Siemionow, who heads the microsurgical research team that performed the face-transplant procedure at the Cleveland Clinic, is pursuing another research track. In her animal lab, she's begun a series of rat experiments designed to trick a host immune system to recognize transplanted tissue as self. She has identified an antibody—a type of protein that links to an invader and repels it—that allows the host immune system to tolerate transplanted tissues without the need for long-term immunosuppression. So far, these rats have achieved immune tolerance for as long as two years.

Siemionow acknowledges that the treatment is not yet ready for human subjects. "We can do a lot with rats and immune tolerance, but humans are so much more complex," she says. Still, she is hopeful the approach will move forward in human clinical trials in about a year.

Progress is invariably slow in this type of research, and Sachs is feeling the pressure, with the number of patients waiting for organ transplants far exceeding the number of available organs. The hope, he believes, lies in xenotransplantation, essentially a process of growing organs from animals that are compatible with a recipient's immune system. But that prospect, Sachs says, "is a longer way off," and would, of course, benefit from just the kinds of advances in preventing organ rejection he's working on.

For now, even when experimental treatments are successful, as they have been so far for Jennifer Searl, there are still no easy fixes. The procedure she underwent was grueling. The initial effect of having her bone marrow partially destroyed prior to surgery—with low-dose chemotherapy, medication and radiation—was very hard on her, as was spending several weeks in isolation after surgery while her immune system was rebooting. It was "an incredibly lonely time," Searl says.

But now that time has been supplanted by what she calls "a completely full, normal life." Searl is a marathon runner and swims on a masters' team. She likes to read, and admits to a penchant for the television show "Gossip Girl." "I just feel so normal," she says. "I don't know what the future will bring. But today, I can say I'm finally free."

And if Sachs's treatment proves to be successful in a larger trial, there's a good chance that more transplant patients may one day be able to say the same thing.

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