Transplanted organs rarely get a hero's welcome in their new home--in fact, they are often attacked viciously by the host's immune system. Researchers have long known that a follow-up infusion of bone marrow cells from the same donor eases the transition, but they haven't known why. Now a report in this month's issue of Nature Medicine may provide an explanation: A key bone marrow protein causes immune cells in mouse transplant recipients to self-destruct. The work could eventually lead to new drugs designed to selectively kill those immune cells that have identified a transplant as foreign.
Scientists have known about the beneficial effects of bone marrow transplants since the late 1960s, but "there really hasn't been much data available to explain what is going on," says immunologist James George of the University of Alabama, Birmingham, an author of the new study. Some researchers believe the infused cells simply provide enough foreign matter to desensitize the recipient's immune system to the donor tissue. Others, including George, suspect that donor marrow is more like a benevolent assassin--triggering the suicide of T cells that attack a transplanted organ.
The T cell's self-destruct program is turned on when a molecule on its surface, called Fas, binds to a protein called Fas ligand. Bone marrow cells have such ligands, so George and co-workers set out to see if they are involved in an assisted cellular suicide that helps organ transplants. With researchers at the Jackson Laboratory in Bar Harbor, Maine, George and colleagues transplanted mouse skin to 19 mice. They destroyed the T cells in 12 mice, five of which received marrow cells from normal mice while seven received marrow from mice with a defective Fas-ligand gene. After 50 days, the skin graft survived only in the five mice given normal bone marrow. Controls and mice with defective Fas-ligand marrow both rejected the graft after about 40 days.
"I think they have a very interesting observation," says University of Toronto immunologist Richard Miller. "Those infused bone marrow cells must play an active role." George says his team hopes the findings will someday lead to safer, more effective transplants: "If we could successfully induce tolerance in patients, the result would be a very large improvement in their quality of life."