Even though rejection of the first transplanted heart had been induced, a second one succeeded.
Published in Nature Communications, the study used transplanted hearts in mice and induced tolerance and then rejection before doing a second transplantation a week after rejection of the initial graft.
The second heart to be transplanted was readily accepted and remained fully functional during the study.
In some human transplant recipients, immune rejection can occur within weeks and further transplants can be rejected even more quickly because of the immune memory - an immune system state of alert.
"Transplantation tolerance appears to be a resilient and persistent state, even though it can be transiently overcome," says Anita Chong, PhD, professor of transplantation surgery at the University of Chicago in Illinois and co-senior author of the study. "Our results change the paradigm that immune memory of a transplant rejection is invariably permanent."
Lifelong immune-suppressing drugs are almost always required to prevent transplant rejection in patients with end-stage organ failure.
Immune tolerance - in which a transplanted organ is accepted without long-term immunosuppression - can be induced in some patients, but with difficulty.
Even after long periods of tolerance, rejection can still be triggered in these patients - for example, by bacterial infection. Doctors assumed that this was because the immune system remembered rejection and prevented tolerance of future transplants.
Immune tolerance was restored once bacteria was eliminated
In the laboratory work on mice, immune tolerance was established but then challenged 2 months later with a bacterial infection. Transplant rejection was triggered in half of the animals.
But the researchers discovered that once the immune system eliminated the bacteria, it spontaneously returned to the earlier state of immune tolerance and accepted another heart transplant.
The animal experiments raise hopes for application in people. "The methods for achieving transplantation tolerance differ between mice and humans, but the mechanisms that maintain it are likely shared," says Dr. Marisa Alegre, co-senior author and professor of medicine at the University of Chicago.
"Our results imply that tolerant patients who experience rejection could be treated with short-term immunosuppressive medications to protect the transplant, and then weaned off once tolerance returns."
"We're now working to understand in greater detail the mechanisms for how this return of tolerance happens," says author Michelle Miller, a graduate student in molecular medicine at the University of Chicago. "We want to find if there are other mechanisms [...] that mediate tolerance and help prevent memory of the rejection."
The authors conclude their paper by stating that they "provide experimental evidence of a transplant outcome that does not follow the rules of allosensitization."
They add that a "memory of regulation can dominate over a memory of infection-triggered rejection."