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Release: Feb. 1, 2002

Researcher now at UI involved in organ transplantation finding

The 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 or death.

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.

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com/.