by Nancy Fliesler
Before Lizzie Stidsen was born, doctors were advising her parents to give up on her. She and her identical twin, Hannah, shared one placenta, but their blood circulations were unbalanced: most of the blood was going to Hannah, while Lizzie's sac had almost no amniotic fluid. "The doctors suggested letting nature take its course and letting her die in utero," says mother Kate McHugh. "But we wanted to give both babies the same chance."
Surprising Kate's doctors, the blood supplies began to equalize later in the pregnancy, and Lizzie survived. But she was born with acute kidney failure, and her scarred, poorly formed kidneys were only about half the normal size. Plans were made for a transplant as soon as a suitable donor could be found.
Although Lizzie had enough kidney function to live, she had gastrointestinal problems that left her severely underweight as a newborn. "We could only feed her in a room with hardwood floors because she vomited so much," Kate recalls. "We had to burp her very gingerly."
Kate learned how to put a nasogastric tube down Lizzie's throat, and after several months of nightly tube feedings, Lizzie began to grow. Her kidneys stabilized, the transplant was postponed, and with a variety of vitamins and supplements, she was a relatively healthy child. But she was often fatigued and had problems with her knees and wrists. "Her body chemistry wouldn't filter stuff out, and it was affecting her bones," says Kate.
Lizzie's growth was also impaired. During early puberty, she endured two years of growth hormone shots, given by Kate every two weeks, but she remains five inches shorter than Hannah.
In 2002, when Lizzie was 12, a blood test indicated that her kidneys were beginning to fail. The family met with William Harmon, MD, chief of Nephrology at Children's Hospital Boston, to discuss a transplant, and the search for a donor was on.
Unlike most transplant patients, Lizzie had an identical twin whose tissue type was likely to match hers perfectly, but Hannah was under 18, so doctors would not accept her as a donor. In 2003, it was decided that Lizzie's father, Don, would give up one of his kidneys when Lizzie became sick enough to need the transplant.
But he wasn't a perfect tissue match, and Lizzie would need lifelong treatment to prevent her body from rejecting his kidney. The family needed to decide what that treatment would be a decision Lizzie would live with for the rest of her life.
In any type of transplant, unless the donor is an identical twin, the recipient's immune system will quickly spot and attack the foreign tissue. During the first few months after a transplant, when rejection risk is highest, most patients receive special antibodies to disarm their T lymphocytes, the white blood cells that initiate the attack. But after this "induction" treatment comes a lifetime of immunosuppressive drugs—usually three or four different medications taken two or three times daily. Included are two kinds of drugs that have been critical in the development of transplant medicine: steroids (such as prednisone) and calcineurin inhibitors (cyclosporin and tacrolimus). Since cyclosporin's introduction in 1982, for example, one-year survival after a transplant has improved from 50 percent to 90 to 95 percent.
But these drugs have disturbing side effects. Both cyclosporin and tacrolimus can cause serious kidney damage. Steroids stunt children's growth and cause weight gain, severe acne and a moon-shaped face. They can change a child's body shape, with fat accumulating on the trunk, upper back, and back of the neck, and cause skin to bruise and cut easily. Cyclosporin makes unwanted hair sprout—girls sometimes develop mustaches—and can coarsen facial features.
As children get older, many begin to resist taking their drugs because of these effects. Others simply become lax, forgetting their medications on the weekends or skipping them when they feel healthy. Harmon has seen adolescent patients wait months or years for a kidney, only to lose it prematurely, and he believes poor drug adherence is largely to blame. The latest statistics show that adolescents have the highest rate of transplant failure of any age group.
The Cooperative Clinical Trials in Pediatric Transplantation (CCTPT), chaired by Harmon, is trying to address this problem. The national study group is working to improve adherence—and outcomes—by eliminating the most damaging immunosuppressive drugs step by step, substituting other drugs or changing the initial induction treatment. "Our goal is to get patients down to two or maybe one drug—the one with the fewest side effects," says Harmon.
Two large CCTPT studies, one still ongoing, have withdrawn or eliminated steroids; a third kept steroids but eliminated calcineurin inhibitors. These approaches generally seem to be working, but some patients have had complications, including early organ rejection.
In fall 2005, a few months before Lizzie's transplant, Harmon laid out the options. Lizzie could receive the standard post-transplant regimen with steroids and calcineurin inhibitors, take her chances with a CCTPT trial in which she might receive steroids, or join a new CCTPT trial called PC01—the most risky trial to date.
PC01 goes where no clinical trial has gone before, eliminating both steroids and calcineurin inhibitors. Instead, before and immediately after the transplant, patients receive an extremely potent antibody called CamPath.
Approved by the FDA for some leukemia patients, CamPath quickly finds and destroys all the lymphocytes in the body—not just those responsible for rejection—wiping out much of the immune system for three to six months. "This is like launching a missile," says Harmon.
The theory was that if you destroy the lymphocytes, then put in a new organ, the new lymphocytes that form won't "see" that organ as foreign. If it worked, Lizzie might only need to take two relatively benign immunosuppressive drugs long-term. But she would need to take heavy doses of antibiotics to guard against infections during the first year, and perhaps longer.
Kate and Don welcomed an option that didn't include steroids, having heard from other parents about severe mood swings and long-term complications like osteoporosis and diabetes.
But Harmon also wanted Lizzie's opinion. "People I met told me how horrible prednisone was," Lizzie says. "I'm not a thin kid, and there's no way I'm going to gain 40 to 50 pounds and have a moon face. One girl got terrible stretch marks and her skin would literally rip."
Lizzie also wanted to avoid calcineurin inhibitors. She knew a girl who had a heart transplant and later needed a kidney transplant because of these drugs. So the family decided to take their chances with PC01 and CamPath.
Lizzie's decision to try CamPath is helping Harmon and other researchers take the first step toward getting transplant patients off chronic immunosuppressive drugs. The ultimate hope is to achieve "tolerance"—acceptance of a transplant while maintaining an otherwise healthy immune system.
Down the hall from Harmon's office, laboratory researchers like Indira Guleria, PhD, are coming up with some promising leads. Guleria, a reproductive immunologist, is finding clues in a major example of immune tolerance: pregnancy. Part of the mother's immune response must be suppressed, Guleria reasoned, otherwise her immune system would spot proteins in the baby that come from the father, interpret them as foreign, and reject the fetus. All pregnancies would end in miscarriage.
"If we could understand the immunologic pathways involved in pregnancy, perhaps we could apply that knowledge to develop tolerance to solid organ transplants," says Mohamed Sayegh, MD, director of the Transplant Research Center, a joint program of Children's Hospital Boston and Brigham and Women's Hospital.
Examining the placentas of pregnant mice, Guleria found abundant amounts of a molecule called PDL1, and showed that it prevents T lymphocytes from infiltrating the placenta—creating a safe haven for the fetus. When the mice received an antibody that blocked PDL1, or were genetically engineered to produce no PDL1, they were more likely to have miscarriages.
"Usually mice have about 10 pups per litter," Guleria says. "But PDL-deficient mice had only two to three pups per litter."
The T lymphocytes that initiate rejection are subject to a variety of "costimulatory" signals that suppress or enhance their activity, researchers are learning. PDL1 sends a negative signal, inhibiting T lymphocyte activity—and preventing pregnant mice from losing their babies.
Hoping to translate her findings to the transplant world, Guleria is now studying diabetic mice receiving transplants of islet cells. In Type 1 diabetes, these insulin-producing cells are destroyed, and several medical centers have begun transplanting donor islet cells into patients as an experimental treatment. However, like any transplant, the cells are eventually rejected, requiring lifelong immunosuppressive therapy. Guleria hopes that if the donor islet cells could be coaxed into making PDL1—through gene therapy or other techniques—they could stave off a T-lymphocyte attack.
Lizzie had her kidney transplant at age 17 in January 2006. By then, her disease had produced a full array of symptoms, one of which, restless legs, led to insomnia and headaches. "I couldn't tire out the twitchiness in my legs," Lizzie says. "I also had calcium and potassium deposits on my eyes, so they were really bloodshot and I was nauseous and really tired."
The night before and the day after her transplant surgery, Lizzie received injections of CamPath to wipe out her immune system. As the antibodies destroyed her lymphocytes, the cells dumped their chemical contents into Lizzie's bloodstream, lowering her blood pressure and causing fever and chills.
The family had been told to expect flu-like symptoms, but Lizzie's reaction, fueled in part by anxiety, alarmed them: She was hot, thrashing her legs, in a rage—"like the Exorcist child," says Kate. "I was just going crazy," Lizzie remembers. "I was angry, so I started throwing things."
The episode lasted a couple of hours. Harmon, who examined Lizzie after she had fallen asleep, was unfazed. "It was frightening for the family, but her reaction is typical and lets us know that the drug is actually working," he says.
Had Lizzie been born 50 years from now, her doctors might have been able to pretreat her for a transplant before birth, while her immune system was still pliable. "When you're exposed to a foreign type of cell as a fetus, you can potentially develop tolerance," explains surgeon Heung Bae Kim, MD, acting director of the Pediatric Transplant Center at Children's. "The body will recognize it as 'self.'"
Kim and collaborators have been inducing immune tolerance in animals by giving them bone marrow transplants in the womb. When things go right, blood stem cells from the donor animal will take up shop in the fetus's bone marrow and proceed to form all types of blood cells, including the T lymphocytes that orchestrate immune responses. The animal is then born with an immune system that accepts the donor's tissue as its own. A second transplant can then be performed from that donor without being rejected.
Even as PC01 breaks new ground by removing both steroids and calcineurin inhibitors from patients' post-transplant regimens, two planned clinical trials would go even further. One trial would test thymoglobulin, an older-generation antibody treatment that has fallen out of use, but may offer an advantage: Mohamed Sayegh, MD, and colleagues showed last October that after it kills T lymphocytes, the immune system re-forms with more "regulatory" T cells. These recently recognized immune cells are important in transplant tolerance. Sayegh hopes that patients given initial thymoglobulin treatment, coupled with careful monitoring, would need only one immunosuppressive drug after the first year.
Another trial would test a drug called CTLA4-Ig that would be injected once a month. Instead of killing T lymphocytes, it tamps down their "rejection" response by blocking signals that activate them. While it would initially be used with a second drug, the eventual hope is that no other drugs would be needed.
And very preliminary research is trying to tackle chronic rejection. Even patients who fully adhere to their immunosuppressants eventually succumb to this insidious, little-understood form of rejection, which begins three or more years after transplantation. "Of all children waiting for a transplant, about 15 percent are awaiting a re-transplant," says David Briscoe, MD, who oversees the Transplant Research Center laboratories at Children's.
Briscoe and colleague Soumitro Pal, PhD, have found that abnormalities in blood vessels may play a role in chronic rejection. "This may be why drugs that target T cells alone have failed to prevent chronic rejection," Briscoe says. The lab's recent work suggests that angiogenesis inhibitors—drugs that suppress blood vessel growth—can delay the process. "Our hope is to some day make chronic rejection go away," Briscoe says.
Using this trick, called in utero tolerance induction, Kim's team has successfully transplanted donor kidneys into two baby pigs without using immunosuppressive drugs. In human patients, Kim thinks the method holds great potential in treating blood disorders that can be diagnosed prenatally, like sickle-cell anemia. A bone marrow transplant after birth can cure these disorders, but requires life-threatening chemotherapy to wipe out the patient's own marrow. But doing the transplant in utero might avoid the need for chemotherapy.
It might also allow patients to accept solid-organ transplants, as it did in Kim's pigs. However, the need for a new organ would have to be apparent very early in the pregnancy—by 13 to 15 weeks. Life-threatening kidney problems usually can't be diagnosed this soon. Heart and lung problems sometimes can, but donors for those organs can't be lined up in advance.
Still, Kim is willing to try in utero tolerance induction in the right situation—an early diagnosis and a fetus so sick that it clearly won't survive, but whose parents want to give it a chance.
"Because of the risks, the outcome would be hard to predict," says Kim. "However, we hope this research will show ways of achieving tolerance that can be applied to the postnatal situation, and even the adult situation."
A year after Lizzie's transplant, she and Don are in good health. Now a senior in high school, Lizzie takes just two immunosuppressants, Imuran and rapamycin. She still needs one drug to prevent infections, but is expected to go off it soon as her immune system recovers from the effects of CamPath. She's had no rejection episodes, and is free of the disfiguring side effects that have plagued her peers. Her main problems are depression and anxiety, which she's battling with therapy and medications.
"I think the feelings I was supposed to be feeling during and after the surgery are catching up with me," she says.
Lizzie herself is scrambling to catch up, having missed half her junior year of high school. A talented fine-art photographer, she's struggling to meet an application deadline at the Massachusetts College of Art.
She also knows that Don's kidney won't last forever. Even if she takes her medications religiously, her transplant will eventually fail due to chronic rejection. Unlike acute rejection, which occurs in the first few years, chronic rejection is more gradual and works by a different immune process that no one yet knows how to counter. Lizzie hopes her experimental treatment will extend the life of her transplant beyond the current average of 15 to 20 years, but there's no past experience to go by.
By the time Don's kidney fails, Lizzie will certainly have better options for post-transplant treatment. And if all goes as hoped, a single, one-time treatment might make her tolerant for life. Harmon and Sayegh are setting their sights on two clinical trials that may advance this possibility, while scientists at the Transplant Research Center are making inroads against chronic rejection [see sidebar above].
"I don't know when we're going to reach it, but I think tolerance is an achievable goal," says Harmon. "If we can get to one drug, you've got to believe we can get patients off all drugs. Your reach has to exceed your grasp."
To learn more about supporting transplant research at
Children's Hospital Boston, please contact Kathleen Corcoran
in the Children's Hospital Trust 617-355-2370 or email@example.com