Cingles Info

Strategies Allow for Drug-Free Organ Transplants in Some, Just One Pill a
Week For Others, Report Researchers at International Congress of The
Transplantation Society
MIAMI, Aug. 26 /PRNewswire/ -- Results of three studies presented today at
the International Congress of The Transplantation Society provide
encouraging evidence that a patient's immune system can be fooled into
accepting a transplanted organ without the need for anti-rejection drugs.
According to one study conducted in India, patients are off the
immunosuppressive drug cyclosporine three months after undergoing living
donor kidney transplantation and an elaborate set of treatments that
included a separate surgical procedure to infuse crushed donor kidney tissue
into their thymus. In another study conducted at the University of
Pittsburgh, a more simple strategy,
but one just as bold, has some patients who received transplants of the
small bowel, one of the must vulnerable organs to rejection, requiring just
one anti-rejection pill once a week instead of the
usual two or three pills two times a day. While in some patients the
researchers had to back off when rejection occurred, they do plan to
continue weaning the patients who so far are doing well, perhaps having them
completely off the anti-rejection drug tacrolimus after one year.
The Pittsburgh team's encounters with rejection and the results of a third
study from Stanford University are a reminder of the formidable challenge of
achieving tolerance, defined as the permanent acceptance of the transplanted
organ without immunosuppressive drugs. Two kidney transplant patients who
were weaned off all drugs within a year of their transplants and who were
drug-free for about five months have since experienced mild rejection
necessitating their going back to low doses of drugs. But the rejection now
treated, their doctors at Stanford are beginning to taper their drugs and
are weaning a third patient in the study as well. At this point, the
numbers are too small to draw conclusions about their results, they say.
Rejection is a common occurrence following transplantation. It merely
signals some degree of activity by immune system cells trying to fight the
presence of the donor organ. Usually an adjustment of doses and drugs can
reverse such episodes, which can vary from mild to serious, and in most
patients, close monitoring of drug levels
keeps rejection at bay. But the drugs that are used to prevent rejection
can have many unpleasant side effects. In addition, they place patients at
risk for developing tumors or serious infections that may be difficult to
treat or be fatal. The drugs also provide no guarantees that the more
insidious, chronic form of rejection will not occur months or years after
transplantation.
More time will be required to determine if any of the patients in these
studies will develop true tolerance. But the results, while preliminary,
show there is promise for patients who must endure a
life-long regimen of immunosuppressive drugs and the attendant side effects
and risks.
At the congress, being held at the Westin Diplomat Resort and Spa in
Hollywood, Fla., Dr. H.L. Trivedi, director of the Institute of Kidney
Diseases and Research Center at Civil Hospital Campus in Ahmedabad, India,
included in his report initial results of 26 patients, each who received an
infusion of their donor's kidney
tissue into the thymus 19 days before the whole organ was transplanted.
The idea behind the procedure is to allow developing T cells being educated
in the thymus to receive a direct and complete introduction to the donor
tissue so that when the cells are mature and circulating in the body they
will be tolerant and less likely to reject the transplanted organ. "It is
expected that these thymocytes will develop anergy to the donor antigens,"
explained Dr. Trivedi.
Ten days before the transplants, the patients also received infusions of
stem cells from their donor's bone marrow into their blood stream and their
own bone marrow. According to Dr. Trivedi, after three months, the patients
were weaned off the drug cyclosporine, but it has been only four months
since the first patient underwent this procedure.
In an earlier arm of the study with longer follow-up, 32 patients who
received living donor kidney transplants following infusions of donor bone
marrow-derived stem cells into their blood stream, bone marrow, liver and
thymus were successfully weaned off cyclosporine one year after the
transplant. The 32 are part of a group of 43 patients who underwent the
multi-step procedure that is based on the same premise as the newer
approach -- to educate the cells to be tolerant of the foreign cells of the
donor. All 43, including those off cyclosporine, have been free of
rejection, and once the 11 remaining patients reach their one-year
anniversary, they too will be taken off
the drug but will remain on low doses of less powerful immunosuppressives,
said Dr. Trivedi.
Patients who underwent routine living donor kidney transplantation without
any special pre-treatment could not be weaned off cyclosporine, and weaning
had to be discontinued in 16 percent of patients who received infusions of
donor bone marrow stem cells into their marrow and blood stream but not the
thymus.
In the Stanford study, weeks before four patients were scheduled for living
donor kidney transplants, their donors, who were not tissue-matched to the
recipients, received doses of a growth factor to boost the number of stem
cells in the blood. (A similar growth factor was used in the Indian study as
well.) The bone marrow was then removed
and saved for infusion into the patients about 11 days after their
transplants. Before receiving the bone marrow, however, patients were
exposed to 10 treatments of irradiation, beginning the day after
transplantation, that was targeted at locations in the body where large
numbers of T cells reside -- the lymph nodes, spleen and thymus. A drug
that depletes immune system T cells, rabbit anti-
thymocyte globulin, was also given after surgery.
According to Dr. Samuel Strober, professor of immunology and rheumatology at
Stanford University School of Medicine, the protocol resulted in
chimerism -- the coexistence of donor and recipient cells -- in three of the
four patients for a period of two to three months, and in two, tests
determined their immune systems were
indifferent to the donor organ. Weaning of all immunosuppressive drugs had
been completed by 12 months in these two patients, but after being off the
drugs for about five months, researchers noted
signs of rejection, which in both cases was treated successfully, and the
patients were returned to low doses of anti-rejection drugs. One patient is
near to complete drug withdrawal and the fourth was never weaned due to an
early rejection.
Importantly, added Dr. Strober, the donor stem-cell infusions did not cause
the potentially life-threatening complication of graft versus host disease,
whereby donor cells attack the recipient's tissues, in any of the patients.
T cell depletion also played an important part in the University of
Pittsburgh study involving 96 recipients of intestine, multivisceral (small
bowel, liver, pancreas, stomach and duodenum), liver,
pancreas, kidney and kidney/pancreas transplants. But instead of receiving
rabbit anti-thymocyte globulin during surgery and at intervals the following
days, patients received a one-time dose just hours before transplantation.
The research team believes that the T cells, those on the front lines of an
immune system attack, need to
be reduced before, not after the introduction of the "enemy," the
transplanted organ. The day after transplantation the team then
administered lower-than- usual doses of tacrolimus, with no other
immunosuppressive agents, not even prednisone, given.
The "new" strategy is actually based on practice and clinical experience of
40 years ago, said Dr. Thomas E. Starzl, professor of surgery at the
University of Pittsburgh's Thomas E. Starzl Transplantation Institute. To
most, it may seem "counterintuitive," he added, because current dogma is to
give patients high doses of immunosuppression as soon as the organ is
transplanted. But under too much immunosuppression, the initial immune
reaction against the donor organ is eliminated, and that prevents a process
called clonal deletion, whereby the activated T cells directed against the
graft
are selectively removed. Without this process, the ensuing steps in the
development of tolerance cannot occur, he explained.
Results presented today by Dr. Kareem Abu-Elmagd, associate professor of
surgery at the University of Pittsburgh's Starzl Institute, involved 22
recipients of small intestine, liver/small bowel and multivisceral
transplants. Results with other organs are being reported at other times
during the congress, which runs through Friday. Seventeen of the 22
patients also received intestinal grafts
that had been irradiated prior to transplantation and donor bone marrow.
Twelve met criteria for weaning off tacrolimus, and at some point after 90
days, the team started the process in a step-wise
fashion, with reductions in the number of doses made every two weeks.
Nine of the 12 patients have been free of rejection since weaning was
initiated, including a recipient of an isolated small bowel that had not
been irradiated, who has been on a once-a-week dose for five months.
Because of close monitoring for immune activation, the researchers were able
to identify four patients in whom rejection would have likely occurred.
Further weaning was delayed in these patients. Three other patients, all
recipients of isolated small bowels, developed rejection that required their
doses be increased and other
agents be administered. One included a patient who had been taking
tacrolimus once every two weeks when the rejection developed. Another of
the three patients, whose rejection occurred at a twice-a-week dose, is now
back to being weaned.
According to the researchers, having their patients take one pill two or
three times a week for up to a year is a reasonable goal before complete
withdrawal would be considered.
Held every two years, the International Congress of The Transplantation
Society is recognized as the field's most important international scientific
meeting. More than 1,600 abstracts covering
basic and clinical science are being presented, and nearly 3,000 surgeons,
physicians and researchers from 71 countries are in attendance. Co-chairs
of the congress are Drs. Camillo Ricordi of the Diabetes Research Institute
at the University of Miami and Domingo Casadei of the Instituto de
Nefrologia in Buenos Aires.
SOURCE International Congress of The Transplantation Society cO:
International Congress of The Transplantation Society;
University of Pittsburgh; Thomas E. Starzl Transplantation Institute;
Stanford University School of Medicine; Institute of Kidney Diseases
and Research Center ST: Florida, Pennsylvania, California, India SU: TDS
SVY
http://www.prnewswire.com