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December 19, 2003

Broad Eradication of T Cells to Prevent Organ Rejection Hampers Efforts to Induce Tolerance

(Philadelphia, PA) – More than 300,000 organ transplants have been performed in the United States since 1988, according to the United Network for Organ Sharing. But an organ transplant, by its very nature, means introducing a foreign body into a person, triggering the immune system to attack the invader, which often results in organ rejection. To prevent this, most transplant recipients take powerful immunosuppressive drugs designed to dampen their entire immune system. While this reduces the risk of organ rejection, it also increases the risk of opportunistic infection, cancer, cardiovascular disease, and diabetes.

For years, researchers have been working to find ways to train the immune system to accept the transplanted organ without suppressing the entire system, an approach called tolerance. Now, researchers at the University of Pennsylvania School of Medicine have discovered that one popular experimental strategy to try to induce immune tolerance—killing host T-cells non-specifically--may not be as effective as once thought, throwing a cautionary light on current practices. Their findings were published in the November 30, 2003 online edition of Nature Medicine and will appear in the journal’s January 2004 print edition. Researchers at Penn and other research facilities are now in the process of identifying which T-cells to target for elimination.

“Tolerance refers to doing something to a patient once or over a limited period of time that makes that patient permanently accept a transplant,” says Laurence A. Turka, M.D., senior researcher on the paper and chief of the Renal-Electrolyte & Hypertension Division of the University of Pennsylvania School of Medicine. The approach can be compared to a vaccine in reverse. While a vaccine is designed to stimulate the immune system to recognize a foreign pathogen and attack it quickly, tolerance is designed to acclimate the immune system to a foreign pathogen (in this instance, the transplanted organ), so it doesn’t attack it.
Researchers try two primary approaches in their attempts to induce tolerance. In one, they replace the recipient’s immune system with the donor immune system via a bone-marrow transplant. In the other, they attempt to inactivate or destroy mature T cells, immune system cells that orchestrate the body’s response to infections or other pathogens.

Regarding the latter strategy, several laboratories, including Dr. Turka’s, have shown previously in mice that inactivating T cells may only work transiently, and therefore it is necessary to kill the T cells which would otherwise attack the transplant. Identifying and eliminating those specific T cells is a difficult process, however, prompting many researchers to simply destroy most T cells. The problem with this approach is that when the T cell supply is depleted the few remaining cells not only divide vigorously, but, in the process, develop characteristics that make them extremely resistant to tolerance. Normally T cells divide infrequently. Depletion stimulates division among the residual cells. As a result, they develop a “memory-like” function that causes further attack on the transplanted organ.

These results, says Dr. Turka, “may make people rethink strategies of inducing tolerance. We believe very strongly that you need to get rid of the particular T cells that react to the transplant. What we think we’ve done now is say that not only do you need to get rid of them, but you need to make sure you don’t get rid of all the other T cells. You need to leave enough reserves so they don’t start proliferating wildly.”

Dr. Turka can be contacted at 215-898-1018 or turka@mail.med.upenn.edu

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PENN Medicine is a $2.2 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System consists of four hospitals (including its flagship Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report), a faculty practice plan, a primary-care provider network, three multispecialty satellite facilities, and home health care and hospice.




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