Navy Doctors Report Transplant Breakthrough

Dr. (Capt.) David Harlan and Dr. (Lt. Cmdr.) Allan Kirk of the Naval Medical Research Institute, Bethesda, Md., announced their discovery during a Pentagon briefing Aug. 5. Following up earlier research, Harlan and Kirk determined that some immune responses can be turned on and off at will.

A special class of white blood cells, T lymphocytes, direct immune responses, Kirk explained. These are the same cells lost by people in the advanced stages of HIV infection. The cells fend off infectious agents but also recognize invading transplanted organs.

The Navy research team discovered, however, some T cell sensors recognize invaders while other, co-stimulatory sensors "marshal the immune system forces to destroy the target," Kirk said. "So if this is a target that you want the immune system to destroy [an infected or cancerous cell, for example], the T cell recognizes that cell through a ... receptor and simultaneously has its on-off switch triggered."

Similarly, drug therapy can be used to re-educate the immune system not to target and reject transplanted organs, even if they are severely mismatched, Harlan explained.

Using rhesus monkeys for their research, Harlan and Kirk experimented with reagents that block the on-off switch so the body's immune system accepts transplanted organs. They gave the monkeys mismatched kidney transplants, then treated some of the monkeys with drugs to prevent the costimulation signal. The other monkeys received no drugs.

The untreated monkeys rejected their new kidneys within five to seven days, but those treated with costimulator blockers experienced no rejections. The researchers stopped treating the monkeys after 28 days, but even six months later, none had rejected the transplanted kidneys.

"This is in stark contrast to conventional immuno-suppression, where drug withdrawal will rapidly lead to rejection, often within a week," Kirk said. Currently, people who receive transplanted organs must accept a lifelong regimen of anti-rejection drugs. The drugs, which are expensive, often have severe side effects and increase susceptibility to infections and tumors.

From additional tests, the doctors learned treatment with the costimulation blocking agents could reverse rejection that already has started.

"We hope that this type of treatment can be developed over the next several years into a method that takes advantage of the body's ability to train its immune system, rather than continuously suppress it," Kirk said. "We feel one step closer to a day when the miracle that transplantation has already become can be combined with safer transient therapy."

Project collaborators included Dr. Tom Davis and other researchers at the Naval Medical Research Institute; transplant surgeon Dr. Stuart Knechtle and his colleagues at the University of Wisconsin-Madison; and scientists from the Navy's civilian partner organizations.

Since immunosuppressant drugs became widely available in 1983, more than 150,000 Americans have received transplants, according to the United Network for Organ Sharing, Richmond, Va. More than 53,000 people currently await transplants.

Harlan's and Kirk's findings were reported in the Aug. 5 issue of Proceedings of the National Academy of Science. The full text is available on the Internet at http://www.pnas.org.