Searching for the secrets of drug-free transplants

October 31, 2000

University of Pittsburgh, through Immune Tolerance Network, to develop tests predictive of transplant tolerance

PITTSBURGH, Nov. 1 -- Researchers at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute have been awarded $728,000 through the Immune Tolerance Network to study a group of transplant patients who are completely off immunosuppressive drugs to see if clues can yield simple laboratory tests predictive of transplant tolerance, the most elusive goal in the field of transplantation. Transplant tolerance, which refers to the state by which a patient's immune system has fully accepted a transplanted organ, is one of the key areas of study of the network, an ambitious $144 million undertaking supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases and Juvenile Diabetes Foundation International.

The Pitt team was selected because of its ongoing contributions in transplant immunology and its body of research that has resulted in about 40 liver transplant recipients in a physician-controlled trial being able to be completely weaned off anti-rejection drugs. The patients have been drug-free for a mean of 6.6 years. Typically, a life-long regimen of anti-rejection drugs, or immunosuppressive drugs, is required to prevent the transplanted organ from being attacked by the patient's immune system. Such drugs can cause serious complications, such as tumor growth, and make patients more susceptible to infections. The risks associated with long-term immunosuppressive therapies are one of the key limiting factors of successful organ transplantation.

The new project will enable further study of these patients, and potentially others, to determine how it is that their transplanted organs continue to be accepted by their immune systems without the aid of drugs, and to identify potential tests that can be predictive of who physicians can wean successfully, tests that may determine and be indicative of transplant tolerance.

"We hope to yield a better understanding of the specific immunological process that occurs in these liver transplant patients who are off all immunosuppression. This will provide a 'roadmap' for clinicians, to help identify those for whom immunosuppression can be safely withdrawn," said Angus Thomson, Ph.D., D.Sc., professor of surgery and molecular genetics and biochemistry at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute and co-principal investigator.

The Immune Tolerance Network envisions findings of this study to have application to other areas of clinical research, from pancreatic islet transplantation to the treatment of multiple sclerosis.

"We are excited because the network fosters the kind of collaboration that could result in implications beyond transplantation. Tolerance assays could support a number of clinical trials and might provide important clues to understanding how tolerance impacts autoimmune diseases as well as allergy and asthma," said Adriana Zeevi, Ph.D., professor of pathology and surgery at the university's Starzl Institute and co-principal investigator with Dr. Thomson.

Dr. Thomson's research interests have focused on the role of dendritic cells in tolerance, while Dr. Zeevi has been performing genetic analyses of key regulatory proteins within the immune system, where small changes in the code may reveal a patient's potential for rejection. The funding will enable both areas of research, as well as others, to be fully explored in order to arrive at a distinct and reliable laboratory profile consistent with the tolerance state.

Other collaborators from the University of Pittsburgh include George Mazariegos, M.D., and Jorge Reyes, M.D. Dr. Mazariegos has been leading the university's weaning study, the only one of its kind. Other institutions that will work with the Pittsburgh team are Case Western Reserve University and the University of Wisconsin at Madison. Collaborators represent a number of other centers, including those that have also identified kidney transplant patients off immunosuppression.

While the project will be looking closely at laboratory studies of patients who are off all immunosuppression, it is not designed to select additional patients for weaning. Researchers nonetheless caution transplant patients that it is ill-advised for them to attempt weaning themselves. Any tapering of immunosuppressive drugs should only be done under the supervision of physicians.

"Our weaning protocol involves a very conservative and closely monitored step-wise process. Under most other circumstances, discontinuing anti-rejection therapies could have devastating effects for the patient," explained Dr. Mazariegos, assistant professor of surgery at the University of Pittsburgh's Starzl Institute.
The Immune Tolerance Network has brought together more than 70 world experts in transplantation, autoimmune diseases and allergy and asthma in order to accelerate new tolerance therapies into clinical use. The announcement of the University of Pittsburgh study, the second of many planned research studies, comes close on the heels of the announcement of an Immune Tolerance Network-sponsored multi-center clinical trial of the highly successful Edmonton Protocol for Islet Transplantation.

The University of Pittsburgh's transplant programs are world-renowned for their cutting edge research contributions and sheer volume of experience. Since 1981, with the arrival of transplant pioneer Thomas E. Starzl, M.D., Ph.D., more than 10,000 organ transplants have been performed at the University of Pittsburgh.

Lisa Rossi
University of Pittsburgh Medical Center

Jeff Matthews
Immune Tolerance Network

University of Pittsburgh Medical Center

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