CONTACT: BECKY SOGLIN
Iowa City IA 52242
(319) 335-6660; fax (319) 384-4638
Release: Feb. 1, 2002
Researcher now at UI involved in organ transplantation finding
main -- and ultimately life-threatening -- problem for patients who undergo
organ transplantation is organ rejection over the long-term, known as chronic
rejection. Immunosuppression drugs are used to help a recipient's immune system
accept and maintain a donor organ. However, the drugs themselves can cause
serious side effects to donated and other organs and contribute to rejection
A study using rats suggests human embryonic stem cells could potentially
be used to allow human patients who receive donated organs to tolerate them
without the need for pre-transplantation immunosuppression drugs or the lifetime
use of such medications after the procedure. The investigation was led by
Fred Faendrich, M.D., Ph.D., a researcher in general surgery and thoracic
surgery at the University of Kiel in Kiel, Germany, and by a new University
of Iowa Health Care physician-scientist, Nicholas Zavazava, M.D., Ph.D., who
was a co-principal investigator of the study while he was a professor and
deputy director of the Institute of Immunology at the University of Kiel.
The findings appear in the Feb. 1 issue of Nature Medicine.
The average survival rate for grafts (donated organs) is approximately 90
percent within the first year for patients treated at most centers in the
United States. However, 10 years after transplantation, only about 50 percent
of the grafts in patients survive, said Zavazava, who now is an associate
professor in the UI department of internal medicine and director of Transplantation
Research, which is based in the department.
"We are very concerned about this survival rate and want to try to
develop new methods of establishing so-called tolerance," he said. "This
essentially means that if you can get your patient into a certain pre-transplantation
condition, when you do the transplant, the patient wouldn't need any immunosuppression
drugs at all."
Bone marrow-derived stem cells can be used in patients to create an environment
that ultimately will accept a donated organ. These cells grow into white blood
cells that accept the donated organ. However, this process involves using
immunosuppression drugs to destroy the recipient's own white blood cells,
which would otherwise attack the introduced bone marrow cells or, later, the
organ itself. This pre-conditioning can be so extreme that some patients die.
Embryonic stem cells can differentiate and grow into all types of tissues,
yet, when introduced, do not cause the body's immune system to attack. These
cells have the potential to develop into white blood cells that will be compatible
with the donated organ. These new white blood cells then can function in a
recipient without the need for immunosuppression drugs, Zavazava said.
In the study, the investigators first injected rats with rat embryonic stem
cells, which then developed into other cell types, including white blood cells.
These cells created a state known as chimerism, which is a mix of tissue from
the donor and tissue from the recipient. The team then transplanted hearts
that were compatible with the rat embryonic stem cells. The researchers determined
that the stem cells succeeded in creating a level of tolerance for the donated
organ, and they found no organ rejection in the animals.
"The mixed state of chimerism is what holds the donated organ,"
Zavazava said. "When we added the heart graft into the rats, it was not
rejected. It's as if the animal's body can say, 'I already know these cells.'
"The importance of our finding is that, with further study, it's a
potential method to deliver embryonic stem cells into a previously untreated
recipient, and the recipient accepts these cells without the need for immunosuppression
drugs," Zavazava added.
Zavazava said the next step would be to investigate the procedure in a larger
animal model. The research would involve developing a new line of non-human
embryonic stem cells.
"We want to better understand the mechanism by which embryonic stem
cells induce tolerance, and also to try the transplants with different organs
such as a kidney or liver," he said. "We also need to determine
how closely the donated embryonic stem cells need to be related to the cells
in the donated organ."
For humans, it would be impossible to derive embryonic stem cells from the
person also donating the organ. An embryonic stem cell bank, similar to existing
bone marrow banks, would have to be set up to meet the need, Zavazava said.
However, given current embryonic stem cell policy and the fact that the
science is only just developing, that proposition is a long way off.
"Of particular concern are the moral and ethical issues that need to
be discussed on a broad basis," Zavazava said.
Implications of the University of Kiel research are significant, given that
nearly 80,000 people in the United States alone are on organ transplant waiting
lists, according to the United Network for Organ Sharing (http://www.unos.org/).
"If we could avoid any one person losing any one single organ, it would
have a strong impact on the number of patients getting valuable organs,"
Zavazava said. "It also is possible that it could improve the incentive
for people to donate because they would see a much higher success rate in
people benefiting from an organ donation."
The University of Kiel study was funded in part by support from the Transplantation
Interdisciplinary Research Group, which Zavazava headed at Kiel, and by a
four-year grant from the German Research Council.
Zavazava, who joined the UI faculty last October, also is a staff physician
and researcher at the Veterans Affairs Medical Center in Iowa City.
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