Monday, December 1, 2008

New procedure, new life

In 2002, Jennifer Searl became the first person in the world to function with a transplanted organ without needing to take immunosuppressive drugs.

Jennifer Searl

Kidney / Bone Marrow

In 2002, Searl became the first person in the world in whom immune-system tolerance to a non-HLA-matched kidney transplant was intentionally induced through a combined kidney and bone marrow transplant. This tolerance allows her to function with a transplanted organ without needing to take any immunosuppressive drugs. Though the procedure was considered risky, for Searl it was the only option.
First TransplantSearl discovered she had kidney disease when she went for a routine camp physical at the age of 12. Her mother had requested blood tests for anemia, and the shocking results were that Searl had only 15 percent kidney function. When she was 13, she underwent a traditional transplant, receiving a kidney from her father. She took some 20 pills a day, all aimed at preventing her body from rejecting the transplanted organ, but the side effects wrought havoc with her body. She developed cataracts and osteopenia - a weakening of her bones - memory loss, facial swelling and an overgrowth of body hair. These conditions were not only threatening her health but were understandably distressing for a teenage girl. Worst of all were the viral warts that burrowed inward from the skin of her feet and legs and were cripplingly painful.

”My entire right foot was covered," Searl explains. "The transplant doctors and dermatologists hadn't seen anything like it. Nothing would make them go away. We tried using lasers to burn the warts off, but that left the bottoms of my feet with second- and third-degree burns, and the warts would grow back when the skin healed."
Immunosuppressive DrugsSearl's doctors scaled back her medications in hopes of moderating the side effects, and the result was chronic organ rejection. As Searl's health faltered, it became clear what she needed was the seemingly impossible: a kidney transplant that would work without immunosuppressive drugs.

Immunosuppressive anti-rejection medications work by interfering with the body's immune system to keep it from destroying the transplanted organ, which the body interprets as a foreign object. Because the immune system, which arises from stem cells in the bone marrow, cannot "learn" to recognize the transplanted organ as a part of itself, patients who undergo organ transplants must take medications for the rest of their lives to suppress their bodies' immune responses.

As Searl experienced in her first transplant, however, long-term use of immunosuppressive drugs leaves patients susceptible to various kinds of infection, can cause a range of metabolic and physiologic changes and increases the likelihood of developing certain cancers. What's more, the conventional treatments currently available are unable to completely prevent chronic rejection.

In light of these problems, enormous efforts have been made to find ways to develop transplant tolerance by "tricking" the immune system into accepting a transplanted organ without long-term use of immunosuppressive medication.
Mixed ChimerismCurrently, a method developed by David Sachs, MD, director of the Mass General Transplantation Biology Research Center, and Megan Sykes, MD, chief of Bone Marrow Transplantation for the Mass General Transplantation Biology Research Center, is considered the most robust way to induce tolerance. In this process, called "mixed chimerism," nonmatched donor and recipient blood cells coexist in a patient's body after he or she receives a bone marrow transplant. Sachs and Sykes have found that the presence of the donor cells, while temporary, creates specific tolerance among newly developing recipient immune cells after the transplant, eventually yielding an immune system that will accept a kidney transplanted from the same donor without the need for the ongoing use of immunosuppressive drugs.
Developing Transplant ToleranceSachs and Sykes have found that the presence of the donor cells creates specific tolerance among newly developing recipient immune cells after the transplant, eventually yielding an immune system that will accept a kidney transplanted from the same donor without the need for ongoing administration of immunosuppressive drugs. At the same time, Sykes also demonstrated the efficacy of mixed chimerism for treatment of certain cancers in animals.

This approach was first tested in six patients with kidney failure resulting from severe multiple myeloma (cancer of the bone marrow) by an Mass General team that included Sachs and Sykes along with Thomas Spitzer, MD, director of the Mass General Bone Marrow Transplant Unit; A. Benedict Cosimi, MD, chief of the Mass General Transplantation Unit, and Nina Tolkoff-Rubin, MD, medical director of the Mass General Kidney Transplantation team. In these patients, combined bone marrow and kidney transplantation from siblings with a perfect human leukocyte antigens (HLA) match was performed to treat both renal failure and multiple myeloma. The patients who developed mixed chimerism successfully acquired tolerance of their transplanted kidneys.
Non-matched TransplantSearl didn't have a perfect HLA match, but a team led by Sachs, Cosimi and Mass General transplant surgeon Tatsuo Kawai, MD, had successfully induced nonmatched transplant tolerance in an animal model by mixed chimerism and were developing a new protocol for which she was a perfect candidate: HLA-mismatched simultaneous organ and bone marrow transplantation. The hypothesis was that by temporarily suppressing Searl's own immune system and introducing donor cells at the same time as the kidney transplant, when her own system returned it would develop specific tolerance to the new organ. If it worked, Searl would be the first person in the world to have a nonmatched transplanted kidney that functioned without immunosuppressive drugs.
No Immunosuppressive DrugsSearl describes the process that arose from this hypothesis as "a month of suffering for a lifetime of normal" and she emphasizes that it was "absolutely worth it." In the fall of 2002, she underwent chemotherapy and local radiation to her thymus to temporarily suppress her immune system. After dialysis to make sure all the chemotherapy was out of her system, Cosimi and Kawai transplanted Searl with her mother's bone marrow and one of her kidneys in a single surgery. She then spent two weeks in a sterilized isolation room, waiting for her new immune system to take hold.
Kidney Transplant Pioneer"Jennifer is a remarkably courageous young woman and truly a pioneer in the field of kidney transplantation," Cosimi says. "After having suffered a series of painful and disfiguring complications from her initial kidney transplant, she chose to be the first person in the world to undergo this tolerance-inducing transplant. Although we were able to describe to her what we had observed in our animal studies, she knew we hadn't yet done it with a patient. Nevertheless, she bravely insisted this was what she wanted to do."

"It was pretty awful at first," Searl admits. "You're in pain and exhausted and very isolated. But everyone made it as comfortable as it could be. The nurses were great. I had Internet access, a VCR, a fridge and an exercise bike. I called it the Ellison 14 spa."
Attitude Influences RecoveryKawai emphasizes that Searl's attitude played a meaningful role in her recovery. "As with many other procedures, a patient's mental strength is vital to getting through this process," he says. "Although the immune suppression we induce is supposed to be a minimally invasive conditioning relative to what patients go through for regular bone marrow transplantation, chemoradiation followed by major surgery is tough. Top that off with a couple of weeks of isolation, and what you have is a much more difficult regimen than regular kidney transplantation."

It was only a matter of weeks before the gamble began to pay off. Searl's blood counts returned to normal, evidence that her new immune system was functioning, and she was released from isolation. A month after surgery, she was discharged from the Mass General on a single, mild immunosuppressant that was carefully withdrawn over a period of months. Searl soon found herself living something quite unexpected: a normal, healthy life, something she hadn't experienced since she was too young to appreciate it.
Feeling FantasticWithin months, she was fully recovered from the rigors of the procedure and working toward her master's degree in library science. Within a year she was exercising regularly, and two years later she had achieved a goal many life-long runners would consider accomplishment enough: a 13.1-mile half-marathon. "It felt fantastic," Searl says. She completed a second half-marathon in May and now has set her sights on swimming in the summer Transplant Olympics and improving her cycling skills to begin competing in triathlons.

Searl is believed to be the only person in the world to undergo both a standard kidney transplant and a simultaneous kidney and bone marrow transplant. She is the first of several patients to date to undergo her particular procedure at the Mass General. Three of them, including Searl, are currently off immunosuppression, and the last patient is now being tapered. "I've done it both ways, and I'll tell anybody who will listen that this way is better," she says. "This whole experience - except for that first month - has been amazing. I think of all the people who worked for decades on this, and I just want to show them that it was all worth it. Dr. Kawai in particular has taken incredible care of me."

As it is, the quality of Searl's life is quite good - a fact that might surprise anyone who hears how much time she still spends at the Mass General. For the past three years, Searl has been putting her library skills to work as a health communications specialist for the Cancer Resource Room at the Mass General. "I'm not surprised to find myself back here," she admits. "At this point, the Mass General has been like a second home to me for more than half my life," she laughs. "I'm way too comfortable with this place!"

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