Friday, December 3, 2010

Conquering Organ Rejection

Breakthrough transplant procedure avoids lifelong dependence on drugs

When Massachusetts General Hospital gave Jennifer Searl the world’s first non-HLA-matched combined kidney and bone marrow transplant in 2002, it was more than just a scientific breakthrough. For Searl, it was the beginning of a new life. Several months after the procedure, Searl stopped taking immunosuppressive drugs, which had caused viral warts on her feet that were so severe she could barely walk. Two years later, she ran her first half marathon.

Dr. David Sachs and Dr. Megan Sykes

For David H. Sachs, MD, and Megan Sykes, MD, both at the Massachusetts General Hospital Transplantation Biology Research Center, and for A. Benedict Cosimi, MD, and Tatsuo Kawai, MD, both in the Mass General Clinical Transplant Unit, Searl’s success was a pivotal moment in their transplant research. Their unconventional approach – transplanting a donor’s bone marrow along with the kidney – proved that the problem of organ rejection could be mitigated without using immunosuppressive drugs, sparing transplant recipients a lifetime of devastating side effects.

Overcoming the Biggest Organ Transplantation Challenges

Six years and five successful procedures later, the Mass General transplant team is beginning a new study in which 15 participants – five at Mass General, followed by 10 at Mass General and at two other centers – will receive kidneys from related or unrelated donors. Funded by the Immune Tolerance Network of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the new grant expands upon the team’s landmark 2008 study involving four Mass General patients who underwent successful combined kidney and bone marrow transplants from related donors.

“We want to extend this wonderful benefit to more patients with kidney disease and to patients with diseases of other organs, and hopefully be able to increase the number of organs that are available in the future,” says Sachs, the principal investigator on the study. In fact, patients in need of kidney transplants have been contacting Sachs and his colleagues in hopes of being chosen to participate in the new study.

Learning How to “Trick” the Immune System

For more than three decades, Sachs and his colleagues have been working to induce immune tolerance of transplanted organs, tricking the recipient’s immune system into thinking the new organ is part of its body. The key, says Sachs, is to prepare the body’s immune system prior to surgery so it doesn’t reject the organ.

Jennifer Searl with her Mass General transplant team

Based on their success with Jennifer Searl, Mass General physicians induced immune tolerance in four recipients from the 2008 study by transplanting bone marrow, along with the needed organ, from a related donor. This process produces a state called “mixed chimerism,” an immune system that blends elements of both the donor and the recipient, allowing the donated organ to be accepted.

“What this innovation will do, hopefully, is make a major difference in how transplants are done,” says Sachs. “Patients can stop taking immunosuppressive drugs and have a normal life.”

Collaboration Fuels Scientific Innovations

Sachs stresses that the success of the new trial, as well as preceding and subsequent studies, relies on the nearly two dozen specialists across Mass General who worked together on this highly complex procedure. “This kind of approach could only be done in a center that has the research capacity and the clinical capacity to carry it out,” says Sachs. “So the combination of a research team, a clinical transplant team, a bone marrow transplant team, and nephrologists, because these are kidney disease patients, has been really instrumental in making this possible. We have established a continuous process of refining, by which we’ve been going from the lab, to the bedside, and then back to the lab again to learn more things to take back to the bedside.”

Mass General has long been recognized as a leader in turning leading-edge science into new clinical applications. The most difficult immunological barrier to kidney transplantation has been a mismatch of HLA (human leukocyte antigen) proteins. Sachs says of the 2008 breakthrough, “We are very encouraged by our initial success in inducing tolerance across the HLA barrier, something that has been a major goal of transplant immunology for years.”

The Transplant Team

Tatsuo Kawai, MD
A. Benedict Cosimi, MD
Thomas R. Spitzer, MD
Nina Tolkoff-Rubin, MD
Manikkam Suthanthiran, MD
Susan L. Saidman, PhD
Juanita Shaffer, BS
Frederic I. Preffer, PhD
Ruchuang Ding, MD
Vijay Sharma, PhD
Jay A. Fishman, MD
Bimalangshu Dey, MD
Dicken S.C. Ko, MD
Martin Hertl, MD
Nelson B. Goes, MD
Waichi Wong, MD
Winfred W. Williams, Jr, MD
Robert B. Colvin, MD
Megan Sykes, MD
David H. Sachs, MD

Successful Transplantation for More Patients

More patients could soon benefit from transplant advances underway at Mass General. Current studies are perfecting techniques by which patients who have already undergone a traditional transplant can receive a bone marrow transplant and eventually stop taking immunosuppressive drugs. Researchers also look forward to a day when the technique can be expanded to all transplantable organs and to organs from deceased donors.

The possibility of using this approach in the pediatric population will be explored once further success has been achieved in adults. “The lack of immunosuppressive drugs would be even more important for children because they have a longer life ahead of them,” says Sachs.

With new scientific approaches leading directly to vastly improved quality of life for a new generation of transplantation patients, there will hopefully soon be more organ recipients like Jennifer Searl, who are not only living longer, but living better and stronger.

The Massachusetts General Hospital Transplant Center stays on the leading edge of medical firsts, offering patients a multidisciplinary approach to organ transplantation and unsurpassed clinical care.

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