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Experimental procedure induces tolerance
to mismatched kidney transplants
Combined organ and bone marrow
transplant allows patients to halt immunosuppression
BOSTON - January 23, 2008 - Four of five patients participating
in a trial of an experimental protocol designed to induce immune
tolerance to HLA-mismatched kidney transplants have been able to
discontinue immunosuppressive drugs. A mismatch of HLA (human leukocyte
antigen) proteins is the most difficult immunological barrier to
transplantation. The report of the study conducted at Massachusetts
General Hospital (MGH) appears in the January 24 New England
Journal of Medicine.
"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, the study's senior
author. "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."
For more than three decades, Sachs and his colleagues have been
pursuing ways to induce tolerance, tricking the immune system into
regarding a donor organ as "self." Over the years the
team has developed an approach in which the organ recipient receives
bone marrow from the donor along with the needed organ to produce
a state called mixed chimerism, an immune system that blends elements
of both the donor and recipient.
In 1998 the team first
used this approach in a woman whose kidney failure had been
caused by the bone marrow cancer multiple myeloma, which can be
treated with marrow transplantation. That patient received both
marrow and a kidney from her HLA-matched sister and was able to
discontinue immunosuppressive drugs about two months later. More
than nine years later she remains healthy, and since then six more
patients with myeloma-induced kidney failure have successfully become
tolerant to HLA-matched transplants through this process
The current study enrolled five patients whose kidney failure resulted
from non-cancerous conditions and who did not have an HLA-matched
living donor. The study protocol begins with therapy designed to
partially destroy the recipient's bone marrow and treatment with
an antibody that reduces the level of T cells, the immune system
component primarily involved in organ rejection. After receiving
the transplanted kidney and bone marrow, patients stay in a relatively
sterile environment for about two weeks, allowing the bone marrow
to regenerate and produce new immune cells that are tolerant of
the donor organ.
The first two patients in the trial were successfully weaned from
immunosuppressive drugs in the months following their transplant,
but the third patient developed early rejection and eventual failure
of the donor kidney. Since the antidonor immune response of that
patient - who subsequently received a successful second transplant
with conventional immunosuppression - was primarily caused by the
immune system's B cells, the study protocol was adjusted to include
an additional antibody targeting B cells. The fourth and fifth patients,
both of whom received the revised protocol, were able to discontinue
immunosuppressives 8 and 10 months after their tranplants. All four
of the successfully transplanted patients continue to have normal
kidney function from two to more than five years later.
As seen in previous animal studies and in some
of the myeloma patients receiving matched transplants, the chimeric
state - the presence in bone marrow of immune cells from both recipient
and donor - was temporary, even though tolerance to donor tissue
continues. Sachs and his colleagues are continuing to investigate
this phenomenon, which they believe may involve some factor provided
by the donor organ. "We have shown in monkeys that the kidney
itself is required to maintain this state that we call peripheral
tolerance, although we still don't fully understand the mechanism,"
he explains.
Sachs stresses that the success of this study and the 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. An additional study involving 10 patients at MGH and 5
at each of two additional institutions is in the planning stages.
The study was supported by grants from the Immune
Tolerance Network; the National Institute of Allergy and Infectious
Diseases; the National Institute of Diabetes, Digestive and Kidney
Diseases; and the Juvenile Diabetes Research Foundation. Additional
co-authors of the NEJM report are Susan Saidman, PhD, Juanita Shaffer,
Frederic Preffer, PhD, Jay Fishman, MD, Bimalangshu Dey, MD, Dicken
Ko, MD, Martin Hertl, MD, Nelson Goes, MD, Waichi Wong, MD, Winfrid
Williams, and Robert Colvin, MD, of the MGH; and Manikkam Suthanthiram,
MD, Ruchuang Ding, MD, and Vijay Sharma, PhD, Weill Medical College
of Columbia University.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine
.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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