A Genetic Rx for Rejection

Organ transplant patients face a catch-22. The powerful drugs that suppress their immune systems and protect their new organs from rejection can cause life-threatening side effects, including high blood pressure, susceptibility to infection and even cancer. Now researchers at the University of Pittsburgh Medical Center have found a link between a patient’s genes and the chances of rejection that could free many patients from lifelong dependence on immunosuppressant drugs.

Physicians have long known that certain people are more prone to deadly rejection episodes than others, regardless of how well a donor organ is “matched” to their bodies. Studying children who received new hearts, a team led by immunologist Adriana Zeevi has now shown that immune molecules called cytokines are a likely culprit. Cytokines kick the immune system into high gear, revving it up to eliminate foreign invaders -helpful if the intruder is a virus, bad if it’s a desperately needed kidney or liver. Zeevi showed that patients whose bodies produce more of a cytokine called TNF-alpha, but less of the cytokine IL-10, were most likely to reject their new organs.

Zeevi’s team has developed a simple genetic test to determine a patient’s cytokine levels and hopes to forecast which patients can tolerate lower drug doses. “If their findings hold up, then they could say ahead of time, ‘You’re going to have a liver transplant and you have this genetic profile, so I’m going to both give you lower immunosuppression and try to wean you from the drugs altogether,’” says Julia Greenstein, chief scientific officer at BioTransplant, a Charlestown, Mass., company that specializes in transplantation technology.

To prove the theory, every transplant recipient at Pittsburgh Medical Center is now given the test-almost 500 patients a year. And George Mazariegos, a transplant surgeon who is working with Zeevi, says that by year’s end he will begin using the genetic screen to select liver transplant patients who are good candidates for weaning from drug treatment. Initial evidence indicates that as many as 30 percent could qualify. Zeevi and Mazariegos predict that profiling transplant patients’ cytokine genes will become standard medical practice in about five years.