Instead of the current practice of giving patients high doses of multiple drugs to suppress the immune system as soon as the organ is transplanted, the Pittsburgh team is giving a one-time dose of a drug that depletes important immune system cells just hours before transplantation and lower-than- usual doses of just one anti-rejection drug beginning the day after transplantation. Ninety days later, if there has been no rejection, the weaning process begins.
A similar strategy, without the deliberate attempt to wean, was in place 40 years ago. Seven of nine recipients of living-donor kidney transplants from that era have been off all anti-rejection drugs for between two and one-half and 38 years. Some stopped taking the drugs on their own. Others were weaned under doctors' supervision. That clinical experience of four decades ago coupled with a modern understanding of what is required for the immune system to accept a transplanted organ without the need for immunosuppression, led to the "new" clinical approach, said Thomas E. Starzl, M.D., Ph.D., at the XIX International Congress of The Transplantation Society.
Since implementing the regimen, which aims to radically reduce and eventually wean patients off all immunosuppression, some transplant recipients of the small bowel, an organ especially prone to rejection, are taking a single anti-rejection drug and only once or twice a week, University of Pittsburgh researchers reported today. Many kidney, liver and pancreas transplant patients being treated under the new philosophy, introduced last year, are on minimal weekly doses as well.
In order to prevent rejection of the transplanted organ, doctors typically provide patients with strong immunosuppressives, often in the form of two or three different agents, beginning at the time the organ is implanted. But that practice, explains Dr. Starzl, eliminates the all-important, initial immune reaction against the donor organ, which under the right circumstances, proceeds to clonal deletion, or selective removal of a subset of T cells that are directed against the donor graft. Without this activation, T cells targeted against the graft will persist, making it forever necessary that patients rely on drugs to protect the organ from being rejected.
"It is these first few days and weeks after transplantation when the seminal mechanism of organ engraftment and of acquired tolerance to donor tissue occur," said Dr. Starzl, professor of surgery at the University of Pittsburgh School of Medicine.
What makes better sense, even though it may seem counterintuitive to most in the field, is to allow the immune activation against the donor organ to occur, but in a subdued fashion so that the clonal deletion of the T cells is both more complete and long lasting. Therefore, it is important to weaken the T cell response before the antigen – the donor organ – is introduced, he explained.
In more than 250 recipients of liver, kidney, kidney/pancreas, intestine and multivisceral transplants, the University of Pittsburgh team administered a single dose of rabbit anti-thymocyte globulin, which depletes T cells, before surgery. Then one day after transplantation, when that immune response had begun, surgeons began giving tacrolimus as the only anti-rejection drug and at much lower doses than is typical.
In 1962 and 1963, while at the University of Colorado, Dr. Starzl treated his nine living-related kidney transplant patients in a similar fashion. One to two weeks before transplantation, the patients received azathioprine, a drug that inhibits the growth of T cells. The same drug was given after transplantation, and prednisone was administered only for the treatment of rejection.
Ironically, in a report of these transplants, Dr. Starzl and his colleagues suggested in a 1963 landmark paper published in the journal Surgery, Gynecology & Obstetrics that in order to better prevent rejection and control rejection, it might be reasonable to give the prednisone along with the azathioprine as standard therapy. In what, in retrospect, was an error, this suggestion was acted upon after performing 45 cases. In addition, pre-treatment with the azathioprine also was soon abandoned as infectious complications prior to transplantation became a problem.
"These decisions have had a lasting influence on clinical practice. After making these changes, no similar cluster of drug-free kidney recipients was produced anywhere in the world for the last 40 years either. We have much better drugs today, and we have a more clear understanding about tolerance. As such, we have come to realize that the way we have been managing patients these last four decades has been self-defeating," stated Dr. Starzl.
Results involving 22 recipients of small intestine, liver-small bowel and multivisceral transplants presented today by Kareem Abu-Elmagd, M.D., professor of surgery at the University of Pittsburgh's Starzl Institute, were among the first in the University of Pittsburgh series to be discussed at the congress, which runs through Friday. Seventeen of these 22 patients also received donor bone marrow and intestinal grafts that had been irradiated prior to transplantation, which the researchers said had little bearing on outcome.
Twelve of the 22 patients, who had no rejection for up to 90 days, were selected for weaning off tacrolimus. The process was conducted in a step-wise fashion, with reductions in the number of doses made every two weeks. Nine of the 12 patients have been free of rejection since weaning was initiated, including a recipient of an isolated small bowel that had not been irradiated, who has been on a once-a-week dose for five months.
Before the new protocol, intestinal transplant patients would have been expected to take two to three immunosuppressives twice, sometimes three times, a day.
"Based on this clinical experience, we are proving that it is possible to decrease an intestinal transplant patient's need for post-transplant immunosuppression. While this is a tremendous step, it would be unwise to proceed too quickly. Having our patients take one pill two or three times a week for up to a year is a reasonable goal before we would consider complete withdrawal," reported Dr. Abu-Elmagd.
Close monitoring for rejection allowed researchers to intervene in four patients before serious damage to the grafts occurred. Their weaning schedule was then readjusted. Three other patients developed rejection that required an increase of their doses and the addition of other agents. All three were recipients of small intestines. One included a patient who had been taking tacrolimus once every two weeks when the rejection developed. Another patient is now back to being weaned after being successfully treated for a rejection that occurred when she was at a twice-a-week dose.
In other related presentations on tolerance, University of Pittsburgh today reported the following:
- Liver transplant patients who have been successfully weaned off immunosuppression have a lower level of a certain type of dendritic cell, reported George Mazariegos, M.D., associate professor of surgery at the Thomas E. Starzl Transplantation Institute. Dendritic cells present antigens to other immune system cells, and this particular type of dendritic cell is thought to accelerate the rejection response. The work is part of a larger effort funded by the Immune Tolerance Network to determine
how it is that the transplanted organs of patients off all immunosuppression continue to be accepted by their immune systems without the aid of drugs. Researchers hope to identify potential tests that can predict who can be weaned successfully and that may also be indicative of transplant tolerance as well.
Myeloid pDC1 is Decreased as Compared to Plasmacytoid pDC2 Lineage in Peripheral Blood of Patients Successfully Withdrawn from Immunosuppression After Liver Transplantation (Abstract 0065) Presentation: 10 a.m., Monday, Aug. 26; Oral Abstract Session 8, Diplomat 4/5 - Reporting on 17 liver transplant patients who were treated under the new strategy involving pre-transplant T cell depletion and single immunosuppressive therapy following transplantation, John J. Fung, M.D., Ph.D., Thomas E. Starzl Professor of Transplantation Surgery, said 14 have been able to be actively weaned. Many are on substantially lower weekly doses than other liver transplant patients not treated under the new protocol, added Dr. Fung, who is also chief of the division of transplantation at the University of Pittsburgh School of Medicine.
Immunosuppression Withdrawal Post Liver Transplantation (Abstract 0099) Presentation: 1:45 p.m., Monday, Aug. 26; State-of-the-Art Symposium 02, Grand West - Dendritic cells, which can both instigate rejection as well as induce tolerance and prolong transplant survival, is a promising area of research, reported Angus Thomson, Ph.D., D.Sc., professor of surgery and molecular genetics and biochemistry at the University of Pittsburgh School of Medicine and the Thomas E. Starzl Transplantation Institute. Harnessing the tolerogenic potential of these cells may help regulate the response against the donor organ and lead to improved outcomes in clinical transplantation. Studies soon to be conducted on non-human primate focusing on a special subset of dendritic cells will be of particular significance in developing strategies of relevance in humans.
Dendritic Cells in Transplant Tolerance and Rejection (Abstract 0120) Presentation: 1:45 p.m., Monday, Aug. 26; State-of-the-Art Symposium 07, Diplomat 4/5
Dr. Abu-Elmagd's talk, Tolerance for Human Intestinal Transplantation (Abstract 0061) is at 10 a.m., Monday, August 26; Oral Abstract Session 8, Diplomat 4/5.
Dr. Starzl is speaking at 12 p.m. on Wednesday, Aug. 28 in a plenary session titled "What's New and Hot in Transplantation" (Plenary Session IV, Grand East/West), at which time he will elaborate on the lessons learned from history and present results of 50 kidney transplant patients who were treated under the new strategy.
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