Weaning Transplant Recipients from Immunosuppressive Drugs

The word "immunosuppression" is used to describe holding back (or suppressing) a person's immune system.

The immune system keeps people from getting sick by attacking "invaders" that can get into the body, like viruses or bacteria. This important function is not something one would normally want to suppress. However, immunosuppression is necessary to treat some medical conditions. One of those conditions is organ rejection after transplantation.

The body's immune system recognizes the difference between its own cells and foreign matter. It just can't tell the difference between harmful foreign cells and those that are helpful, such as the foreign tissues in a transplanted organ.

Transplant recipients commonly experience organ rejection because of this. "Rejection" means that the body's immune system attacks the donor organ's cells, reacting to them as if they were harmful. Medications that curb the immune system (called immunosuppressants) are essential for transplant recipients, because they prevent and treat rejection. The discovery of immunosuppressants — and the advances still being made — allow many transplant recipients to live longer, healthier lives.

Nevertheless, immunosuppression creates a new set of problems. People with suppressed immune systems are less likely to reject their transplanted organs, but also less able to fight off harmful "invaders." This leaves them vulnerable to infections and some types of cancer. Immunosuppressive drugs (also called "antirejection drugs") can also cause other side effects. Doctors use different combinations of medications, and work to maintain a delicate balance in each patient, to try to reduce the chances that an organ will be rejected.

At UPMC's Thomas E. Starzl Transplantation Institute, specialists have been exploring the question of why some patients need less medication to accept transplanted organs than others. Dr. Starzl heads research at the institute.

A new technique being developed at the institute involves carefully weaning patients from immunosuppressants. While UPMC's transplant doctors haven't yet learned how to completely wean transplant recipients from antirejection drugs, they are getting close.

In standard therapy, the patient receives a massive dose of antirejection drugs immediately after transplantation. This powerful treatment is employed in hopes of avoiding rapid (or "acute") rejection. This kind of rejection most commonly develops in the first year after a transplant. After such high-dose initial immunosuppression, the patient is put on a lifelong course of relatively high doses of antirejection drugs to prevent long-term ("chronic") rejection.

However, in certain patients, the immune system naturally accepts the transplanted organ without immunosuppression. After studying these people for years, UPMC researchers came to believe that, in these patients, the immune cells that would normally attack the organ are themselves eliminated by a second, beneficial, immune attack.

The problem with high-dose treatment, the scientists reasoned, might be that along with preventing the "bad" attack of immune cells against the organ, it prevents the "good" elimination of those attacking cells. A method for preventing acute rejection that wouldn't affect the good elimination, then, might make many more patients' bodies able to accept their transplants with less or even no long-term immunosuppression.

Dr. Starzl and colleagues developed a method for preventing acute rejection that uses a pretransplant treatment with a "guided missile" drug that only affects the immune cells that attack the transplanted organ. Because this drug — called an antibody-based drug — doesn't prevent elimination of the transplant-attacking immune cells, it lowers the chances of acute rejection while allowing the patient's body to more effectively accept the organ. After the initial antibody-based therapy, doctors give these patients smaller and smaller doses of conventional antirejection drugs to try to find minimum dose necessary to prevent rejection.

Today, all patients at UPMC with solid organ transplants receive the improved protocol. While the investigators say they need to collect more long-term data to thoroughly document the method's effectiveness, its contribution to longer-than-typical survival times at UPMC and lower rates of side effects indicate that they're on the right track.

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