February 1, 2008

Experimental procedure induces tolerance to mismatched kidney transplants

Four of five patients participating in a trial of an MGH-developed protocol to induce tolerance to mismatched kidney transplants have been able to discontinue immunosuppressive drugs. "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," says David H. Sachs, MD, director of the MGH Transplantation Biology Research Center (TBRC) and senior author of the report appearing in the Jan. 24 issue of the New England Journal of Medicine (NEJM).

For more than three decades, Sachs and his colleagues have been pursuing ways to essentially trick a recipient's immune system into regarding a donor organ as "self." Over the years the team has developed an approach in which the recipient receives the donor's bone marrow along with the needed organ, leading to an immune system that blends elements of both the donor and recipient. Since 1998, the team has successfully used this approach in seven patients who received immunologically matched organs to treat kidney failure caused by the bone marrow cancer multiple myeloma, for which marrow transplantation is a standard treatment.

The current study enrolled five patients with kidney failure from noncancerous conditions who did not have perfectly matched living donors. Before the kidney and bone marrow transplant procedures, patients were treated to partially destroy their bone marrow and reduce the level of T cells, the immune system component primarily involved in organ rejection. After one participant rejected the donor kidney, the protocol was adjusted to also target the immune system's B cells. All four of the successfully transplanted patients continue to have normal kidney function from two to more than five years later.

"While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced," says Sachs. He stresses that the success of this study and of preceding and subsequent investigations relies on the multidisciplinary team of researchers from the MGH Transplant Center. Key team members are surgeons Tatsuo Kawai, MD, lead author of the NEJM report, and A. Benedict Cosimi, MD, chief of Transplantation Surgery; Thomas Spitzer, MD, director of the Bone Marrow Transplant Unit; Nina Tolkoff-Rubin, MD, medical director of Kidney Transplantation; and Megan Sykes, MD, chief of the Bone Marrow Transplantation Section and associate director of the TBRC.