| Departments — Benchmarks | Spring 2008 |
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Adjusted to Fit Research from a team at Massachusetts General Hospital, however, may have struck upon a way to ensure tolerance of kidney transplants without the long-term assistance of immunosuppressive drugs. The team’s innovation relies on a quick succession of therapies that trick the immune system into accepting the new tissue as friendly rather than foreign. And perhaps most promising of all, the method is the first to work for patients and donors who were immunologically mismatched, a situation that can complicate transplantation efforts. The senior researcher for the MGH team was David Sachs ’68, the Paul S. Russell/Warner–Lambert Professor of Surgery and director of MGH’s Transplantation Biology Research Center; the team also included Nina Tolkoff-Rubin ’68, a professor of medicine and director of hemodialysis at the hospital. Their report appeared in the January 24 issue of the New England Journal of Medicine.  Preparation Is Everything The team designed the study with pre- and postconditioning routines that they hoped would create a temporary state in which bone marrow stem cells from the donor would mix easily with those of the patient. The stem cells in a person’s bone marrow spawn an array of other cell types that populate the body’s immune network. In the chimeric state the researchers sought to induce, the bone marrow stem cells of the patient would form an alliance with introduced bone marrow cells from the donor. The mixed cells could then work to broker an amiable coexistence between the new tissue and the body’s immune sentinels. If all went well, the patient’s immune system would be tricked into accepting the donor kidney forever. To ease this transition, the team preconditioned each patient with a regimen that used chemotherapy to partially destroy patients’ bone marrow; an antibody to disable immunologically active T cells, which form in the thymus; and irradiation of the thymus to further suppress T cells. After transplantation and an infusion of donor bone marrow, patients were isolated for two weeks in a sterile room to allow cells in the bone marrow and the immune system to regenerate. The team enrolled five patients with end-stage renal disease who were scheduled to receive a kidney from an immunologically mismatched parent or sibling. The first two patients responded well to the preconditioning, transplantation, postsurgical isolation, and a nine- to fourteen-month weaning from immunosuppressive drugs. A third participant, however, rejected the transplanted organ and had to undergo a second transplant. This rejection might have clouded the team’s effort had they not discovered the patient’s B cells had rallied to fight the new organ’s presence. In most cases, B cells, which develop in the bone marrow, depend on T cells to activate. In this patient, reactive B cells may have already existed. By revising the plan to include a B-cell–depleting antibody in the preconditioning protocol, the team used the regimen successfully for the final two participants. Of the four patients for whom the study regimens worked, all have had stable renal function for two to five years. “This marvelous work exemplifies the progress occurring in the field,” says Joseph Murray ’43B. “It is simply mind-boggling the way advances have manifested themselves in the decades since the first solid-organ transplantations.” In 1954, Murray was surgeon for the team that performed the first successful human organ transplant. Four decades later, Murray, together with E. Donnall Thomas ’46, received the Nobel Prize in physiology or medicine for pioneering work in the field of organ transplantation. Matched Set Across the country, another HMS alumnus has broken new ground in the field. Samuel Strober ’65 was senior researcher on a Stanford team that also reported findings on immune tolerance of organ transplants in the January 24 issue of the New England Journal of Medicine. Unlike the MGH effort, the Stanford team focused on transplantations involving matched donors and patients. The study relied on a post-transplantation regimen of lymphoid irradiation and antithymocyte globulin, an antibody that fights tissue rejection by blocking the actions of T cells, to adjust each patient’s immune system to accept the new tissue. After ten days of the regimen, patients were infused with blood stem cells from a compatible donor and a state of persistent chimerism was achieved. Of the six patients in the study, one has been off all immunosuppressive drugs for more than two years. According to MGH’s Sachs, the studies’ findings could offer patients lives free of the problems—and cost—of immuno-suppressive drugs. Ann Marie Menting is associate editor of the Harvard Medical Alumni Bulletin Photo caption (mid-story): Massachusetts General Hospital's research team inlcuded (clockwise from left) David Sachs, Tatsuo Kawai, Thomas Spitzer, Megan Sykes, Dicken Ko, Benedict Cosimi, Jennifer Searl (the first study patient), and Nina Tolkoff-Rubin. Photo: Paul Tearle/Getty Images (story top); Joshua Touster |
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