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University of Pittsburgh Researchers Identify Subtype of Cell That Promotes Organ Transplant Acceptance

CHICAGO, May 15, 2001 — In one of the few studies of its kind, researchers from the University of Pittsburgh's Thomas E. Starzl Transplantation Institute have found that a subtype of dendritic cell plays a key role in preventing organ rejection and may be associated with transplant tolerance, the long-term survival of a transplanted organ without the need for immunosuppressant drugs.

Researchers will now be looking to see if the same cells are present in liver and kidney transplant recipients who have been successfully weaned off immunosuppression, patients who are essentially tolerant of their organs.

The findings are significant because dendritic cells, a rare type of white blood cell that is present in all tissues, have been thought only to be involved in prompting the rejection process, reported Peta J. O'Connell, Ph.D., at Transplant 2001, the joint meeting of the American Society of Transplantation (AST) and the American Society of Transplant Surgeons.

Dendritic cells are known for their ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen. But according to Dr. O'Connell, some dendritic cells apparently regulate the immune response, determining that a frontline attack by T cells can be unwarranted.

Dr. O'Connell, a visiting research instructor working with Angus W. Thomson, Ph.D., D.Sc., reported that a pre-transplant infusion of lymphoid dendritic cell subtypes derived from tissue such as the spleen, allowed for prolonged survival in a mouse heart transplant model, even without the use of drugs to control rejection. In contrast, myeloid dendritic cells accelerated the rejection response.

"The lymphoid-derived dendritic cells somehow disarm immune system T cells from doing their part to attack the donor organ possibly by causing either their death or limiting their proliferation," explained Dr. O'Connell, who received an AST Young Investigator's Award for her work.

Based on these studies, the researchers plan to see if these "good" dendritic cells are present in liver and kidney transplant recipients who are off all immunosuppression as part of a larger effort to identify laboratory profiles and tests consistent with tolerance.

Through the Immune Tolerance Network, an ambitious undertaking supported by the National Institutes of Health and Juvenile Diabetes Foundation International, Dr. Thomson and Adriana Zeevi, Ph.D., are leading this unique study to better understand the specific immunological process that occurs in transplant patients who are off all drugs. Specifically, Drs. Thomson and Zeevi are looking at the role of dendritic cells in tolerance as well as key regulatory proteins within the immune system, where small changes in the code may reveal a patient's potential for rejection.

"This will provide a 'roadmap' for clinicians, to help identify those for whom immunosuppression can be safely withdrawn," said Dr. Thomson, professor of surgery and molecular genetics and biochemistry at the University of Pittsburgh School of Medicine and the Thomas E. Starzl Transplantation Institute.

"We'd like to identify the cellular and molecular clues so that assays, or very simple laboratory tests, can be developed that would be predictive of tolerance," added Dr. Zeevi, professor of pathology and surgery at Pitt's School of Medicine and the Starzl Transplant Institute.

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