Transplant Drug Blocks Tolerance

Scientists have new clues about why a common immunosuppressive drug, cyclosporin, may be sabotaging a promising new therapy for organ transplants. The reason seems to be cyclosporin's competing effects: While it keeps the immune system from attacking transplanted organs, it also blocks the suicide of immune system cells, a kind of cell death that appears to help the body tolerate foreign tissue. The findings, reported in this month's Nature Medicine, should help lead to safe ways to test the tolerance-inducing therapy in people.

A healthy immune system recognizes and destroys invaders, but scientists have known for almost 50 years that in some cases animals' immune systems can be persuaded to accept certain foreign proteins--a process called "tolerance"--yet still destroy pathogens. If researchers could repeat the success in human patients, organ recipients might not have to spend their lives on powerful immunosuppressive drugs, which leave them vulnerable to infections and cancer.

Experiments with specially designed antibodies in monkeys have looked promising, but common immunosuppressants, including cyclosporin, seemed to foil the tolerance therapy. That has made it difficult to design human trials; potential subjects would have to forego immunosuppressive drugs that are standard practice for transplant patients.

Transplant physicians Laurence Turka of the University of Pennsylvania and Terry Strom of Beth Israel Deaconess Medical Center and their colleagues suspected that the forced suicide of certain T cells might be a key step in immunotolerance. To confirm their hunch, the researchers attempted to induce tolerance in two strains of transgenic mice, both of which have mutations that prevent T cell apoptosis, or programmed cell death. The researchers found that tolerance-inducing therapies that work on normal mice fail in the mutant strains.

In another set of experiments, the researchers observed that cyclosporin, which prevents T cell suicide, also blocked the development of tolerance. But they also found that rapamycin, a drug that encourages apoptosis, allowed them to induce tolerance to skin grafts in mice--usually a difficult feat.

This finding provides important insights into the development of tolerance, says immunologist Herman Waldmann of Oxford University, United Kingdom, and also should help scientists design better human trials for tolerance-inducing therapies. Strom agrees: Now that they can explain why cyclosporin blocks tolerance, "it takes us out of the gridlock situation where some people might insist that [cyclosporin-like drugs] must be part of every protocol," he says.