Laurie Barclay, MD

May 5, 2003 - Editor's Note: A new protocol for organ transplantation developed at the University of Pittsburgh Medical Center (UPMC) in Pennsylvania may result in significant improvements in quality of life and long-term survival, according to a report in the May 3 issue of The Lancet.

Investigators from UPMC's Thomas E. Starzl Transplantation Institute treated 82 patients with rabbit antithymocyte globulin for T-cell depletion just before transplantation, and with only one immunosuppressant after transplantation instead of the usual two- or three-drug cocktail. Of the 82 patients, 50 were recipients of a kidney transplant (including 10 who received kidney/pancreas), 17 of liver, 11 of small bowel, and four received a pancreas transplant.

For posttransplant immunosuppression, the investigators administered tacrolimus at markedly reduced levels and continued to taper the dose even further, aiming for the mininum amount of immunosuppression sufficient to avoid graft rejection.

In patients for whom it was thought to be safe, the process of weaning began about four months after transplantation. If patients developed rejection episodes, steroids were added, or more potent immunosuppressants if needed, for as brief a period as possible. After the rejection episode resolved, many patients were able to return to the single-drug regimen and to begin the weaning process again.

At 13- to 18-month follow-up, 78 (95%) of 82 organ recipients were alive, and graft survival was 88%. Of the 72 recipients with functioning grafts, 43 were on "spaced doses" of tacrolimus, including 11 patients on one dose per week, 15 on twice-weekly doses, 11 on doses three times a week, and six patients on alternate-day tacrolimus. Based on animal studies, the authors do not recommend discontinuing tacrolimus or tapering it lower than one dose per week.

To learn more about this revolutionary approach, Medscape's Laurie Barclay interviewed lead author Thomas E. Starzl, MD, PhD, a professor of surgery at UPMC, and a pioneer in transplantation who has treated some of the longest-surviving kidney recipients to date.

Medscape: What was the rationale behind this approach?
Dr. Starzl: It was the discovery of the mechanism of organ engraftment, which was a big enigma before. The seminal clue was discovered 11 years ago in a large group of patients who survived up to 30 years after they were transplanted at the University of Colorado in the early 1960s. We studied 30 patients with the longest survival and found donor leukocyte chimerism in all 30. That was the starting point for a long-term series of studies dealing with acquired tolerance.

Dr. [Rolf] Zinkernagel, who was a Nobel Prize Laureate in 1998, and I began studying how the particular kind of immune reaction that rejects grafts also fights infections similar to tuberculosis. One feature of that type of response is acquired tolerance. We described it in the New England Journal of Medicine in December of 1998, then in December of 2001 in Nature Reviews: Immunology we discussed how it might be applied clinically. The recent Lancet article describes our experience with this technique, and now we have close to 700 patients we've treated this way. It's state-of-the-art.

Medscape: Would it be fair to say that it's something of a paradox - that the same immunosuppressive drugs that give excellent graft survival have a negative effect on the induction of donor-specific transplantation tolerance?
Dr. Starzl: Yes, you've crystallized the message exactly. One principle is pretreatment; and the second principle is that paradox you've just described. Immunosuppression is a double-edged sword. It's necessary, but it's antitolerogenic if you give too much. Pretreatment weakens overall immune reactivity before the graft arrives, decreasing the response to the donor to a more readily deletable level. Clonal exhaustion and deletion is the essential mechanism of acquired tolerance. If you want tolerance, you need to allow that mechanism to go forward, but not enough to lead to rejection.

Medscape: How do outcomes with this new protocol differ from those with conventional immunosuppression?
Dr. Starzl: It depends on how you define outcome. Patient and graft survival are at least as good. Even with conventional immunosuppression, in the short-term, graft survival has improved extraordinarily over the years. The real issue is what the five- to 10-year survival will be, which hinges on the control of chronic rejection.

Medscape: What effect do you anticipate that this protocol will have on the development of chronic rejection?
Dr. Starzl: The follow-up is not yet long enough, but we are certain that it will ultimately reduce chronic rejection. Many have predicted that by treating in such a light way, we should see chronic rejection down the line, but we're not seeing that even though we're close to two years out. This strategy is fundamentally designed to avoid chronic rejection. To use your word, it's a paradox, but it makes sense once you understand the mechanism.

One of the most interesting aspects is that this strategy is not organ-specific. One-year survival is typically dismal for intestine transplants, but it's better in our series. So far, our strategy also looks better in lung transplantation, although our follow-up is too short to have included these patients in our Lancet paper. Typically, five-year graft survival in lung transplants is only 40%. Of those patients who survive five years, 35% to 40% have renal failure due to heavy treatment with calcineurin inhibitors.

The overriding complication in lung transplantation has been obstructive bronchiolitis obliterans (OBO), which is thought to be a manifestation of chronic rejection. We suspect it relates to prolonged immunosuppression. We started using our protocol on lung transplant patients about one year ago, and we have 30 thus far. We haven't seen any OBO yet, so we're hoping this strategy will revolutionize lung transplantation.

Not only is our protocol not organ-specific, but another interesting aspect is that it's not drug-specific either. We like the drugs we're using, but you can substitute other drugs. The strategy is based on the biologic behavior of the adaptive immune response.

All major, sweeping advances in transplantation until now have depended on the introduction of more and more potent drugs: azathioprine, then cyclosporine, then tacrolimus. With each new drug, there's been a big increase in survival. Now, we can just use whatever drugs we have on hand - this step is not dependent on new drugs.

Medscape: Is there any way to identify those patients who can be safely tapered off immunosuppressants?
Dr. Starzl: We're working on it. We have quite a few patients on only one dose a week, but we've stopped there for now. It's a very important question, but so far we've had to do it by trial and error.

Medscape: Is any additional research needed before this protocol becomes an accepted standard of care?
Dr. Starzl: It's an accepted standard of care right now, and it's been approved by our oversight committees. We're applying principles that have always been there but have not always been applied, or perhaps have even been ignored. The underlying principle is very simple. The empirical formula has been to start with high doses of immunosuppression, then to decrease chronic immunosuppression to the lowest level consistent with long-term allograft survival. If that lowest level is an infrequent as one dose per week, it's not really a change in management.

Now if you stopped it altogether, that would be the next step. Doses as infrequent as one per week could have a beneficial effect, based on animal models. If you omit that one dose per week in rats, the animals slowly develop chronic rejection. That final step has to be taken with more caution than all the steps that have led up to it.

When you look at the longest survivors of kidney transplants in the world, we should have learned lessons from them that would make this strategy seem less revolutionary now. Of the eight longest survivors who are still living, plus one who was murdered in a love triangle and had a completely normal kidney graft at autopsy, seven were off drugs completely for 38 to 39 years. These patients were pretreated for two weeks with Imuran, then after transplantation, they received Imuran for as brief a period as possible, with prednisone given only for acute rejection.

We abandoned this approach back then because of acute rejection, which seemed like a bigger problem at the time than chronic rejection, which could come on gradually about a year later. So we advanced high-dose steroids to the time of surgery instead of reserving them for acute rejection, which was our mistake.

Other institutions followed our lead, and it's been a widely adopted policy of immunosuppression ever since. We've all seen similar problems with liver transplantation. High-dose steroids prevent acute rejection, but they increase the problem of chronic rejection.

Medscape: Could your findings have implications for other treatment protocols involving immmunosuppression, such as treatment of multiple sclerosis, connective tissue diseases, or other autoimmune diseases?
Dr. Starzl: I'm sure they could, but I can't say exactly how. It's an interesting question. In transplantation and in the autoimmune diseases, we're trying to switch off immunity. The mirror-image problem is with immune deficiency diseases like HIV, where you'd like to do exactly the opposite. So our findings could have multiple implications. The controlled governance of immunoreactivity versus nonreactivity could also be applied to other clinical problems, like tumor surveillance and self-nonself discrimination.

Lancet. 2003;361:1502-1510