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Pilot Studies of Liver Transplant Patients off All Anti-Rejection Drugs Suggest They Have an Altered Cellular Profile

WASHINGTON, June 2, 2003 Liver transplant patients who are off all immunosuppression and those who are undergoing withdrawal of their anti-rejection drugs have higher concentrations of a special immune system cell than those patients who have failed attempts at weaning or who have a history of organ rejection, report University of Pittsburgh researchers. Those off drugs have the same cellular profile as normal, healthy volunteers, who the researchersalso studied.

Results of the study are published in the June issue of the American Journal of Transplantation and are being presented today at the American Transplant Congress, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation running through June 4 at the Marriott Wardman Park Hotel in Washington, D.C.

The researchers hope the findings will bring them one step closer to developing a simple blood test predictive of transplant tolerance - the immune system's full acceptance of a transplanted organ - and of which patients can be successfully weaned off all drugs. However, the researchers caution that further studies will be needed to verify their results.

"Developing such a test or series of tests would be of considerable value in identifying those patients who might be safely weaned off anti-rejection therapy. Our finding a higher incidence of a subtype of a certain dendritic cell in our weaned and nearly weaned patients is a positive step toward this goal," said lead author George Mazariegos, M.D., associate professor of surgery at the Thomas E. Starzl Transplantation Institute and the University of Pittsburgh School of Medicine.

Looking for the presence of different kinds of dendritic cells, the researchers found that patients off all anti-rejection drugs and those in the process of drug withdrawal had significantly more of a beneficial kind of dendritic cell and fewer numbers of the more harmful dendritic cells, a cellular profile that was similar to normal, healthy non-transplant patients who served as a control group. Compared to those who required daily doses of anti-rejection drugs - those who failed at being weaned or who had a history of rejection episodes - the patients off drugs or nearing that target also had a much higher ratio of the good cells to bad cells.

These so-called beneficial dendritic cells are immature or precursor dendritic cells that derive from plasmacytoid T cells (pDC2). While dendritic cells, a rare type of white blood cell that is present in all tissues, are usually known for their ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen, not until recently did researchers identify subtypes like the pDC2 that have the opposite effect. These appear to regulate the immune response and determine that a frontline attack against the organ by T cells is unwarranted. "It is quite exciting to identify the presence of this dendritic cell subtype, which we have noted in laboratory models, in patients who by virtue of their being off immunosuppression are tolerant of their transplanted organs," stated Angus Thomson, Ph.D., D.Sc., professor of surgery and immunology at the Starzl Institute, University of Pittsburgh School of Medicine, and senior author.

The published pilot study involved six patients who had been weaned for a mean of 3.3 years, the longest for nearly eight years. Of these, two had been weaned through a physician-controlled protocol, three were taken off the drugs because of serious infectious disease concerns, and one patient had stopped taking the drugs on his own. A second group of patients consisted of 23 patients undergoing the weaning process, and the third group was comprised of 11 patients taking maintenance doses of immunosuppression. Six of these 11 had failed at weaning and five had a history of rejection episodes. Thirteen healthy non-transplant patients served as controls.

At ATC, Dr. Mazariegos is reporting update results that were obtained in eight weaned patients, 26 patients in the process of being weaned and 16 patients who required maintenance immunosuppression. Of the weaned patients, three were taken off for emergent reasons, three were weaned through the protocol and two were noncompliant patients who stopped on their own.

According to the authors, their findings involving dendritic cells, and those published by the team last year that looked at genetic profiles of key regulatory proteins that regulate the immune system, are the first to definitively give clues to the make-up of patients who are able to be off all immunosuppression.

"While the initial results indicate there may be some correlation with the presence of 'good dendritic cells' and immune unresponsiveness, a longer, more complete investigation must now be performed if these cells are to be validated as a surrogate marker of tolerance," said Terry Strom, M.D., co-chair of the Immune Tolerance Network (ITN) Assay Group.

To determine the validity of the dendritic cell profile as a possible test to predict successful weaning, the researchers plan to examine a larger group of liver transplant patients in whom weaning is being considered.

Typically, a life-long regimen of anti-rejection 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.

This study was performed as a project of the ITN, a seven-year clinical research project headquartered at the University of California, San Francisco and supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation.

Dr. Thomson is principal investigator of the Pittsburgh-based ITN study and Dr. Mazariegos is a co-investigator. Other researchers include Adriana Zeevi, Ph.D., co-principal investigator, and Jorge Reyes, M.D., a co-investigator.

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