Researchers show non-Matching transplant induces long-Term blood type tolerance

Helen Branswell

Canadian Press

October 24, 2004

TORONTO (CP) - Children who receive a non-matching blood type heart transplant in early childhood appear to develop long-term tolerance for the donor's blood type, a study shows.

The work, led by researchers at Toronto's Hospital for Sick Children, raises the possibility scientists may be able to learn how to induce tolerance in older patients, creating a world in which the first available organ could go to the person in greatest need, regardless of blood type.

"It may be possible to expand the potential applications of this strategy to older patient populations, which could result in decreased mortality for patients awaiting transplantation and increased usage of donor organs," the team wrote in their paper, to be published Monday in the journal Nature Medicine.

The Sick Kids group first showed in 1996 that young children could accept a heart transplant from a donor of an incompatible blood type. They reported that groundbreaking work in 2001 in the New England Journal of Medicine.

The procedure, now known as the Toronto protocol, has been done on at least 48 children around the world, 20 of whom were operated on at Sick Kids. Of the Sick Kids patients, three have died. But their deaths were not related to problems caused by their incompatible blood-type transplants.

Technique pioneer Dr. Lori West says the success of the work is hugely rewarding.

"Even though it's a tiny group of patients worldwide, they were patients who had virtually no hope of survival. And so the fact that this can be offered to children is personally a very gratifying thing to see," said West, principle investigator for the study.

The team - from Sick Kids, the University of Miami School of Medicine and the Mayo Clinic - used blood samples from 13 recipients of non-matched hearts to draw their conclusion.

They found a child with the O blood type who was given a B blood type heart did not go on to develop antibodies to B blood, as an O child normally would. Similarly, an O-type child who received an AB-type heart would not develop antibodies to A, B or AB blood.

An adult who receives an organ from a donor of an incompatible blood group would develop what's called hyperacute rejection - a violent response where the body attacks the organ as foreign. It leads to death of the organ and generally the recipient as well.

But in very young children, the transplant appears to reprogram their immune systems to view both their own blood type and the donor's blood type as their own, West said.

"What we've shown here is that over the subsequent months and years after transplantation, they never do develop antibody to the donor blood type," said West, a cardiologist and transplant immunologist.

"It's as if their immune system thinks that their donor blood type is a 'self' blood type."

West said the findings prove for the first time in humans a principle that researchers first identified in mice more than 50 years ago.

They reported that the immature immune system of newborn mice would not develop antibodies on exposure to foreign blood types.

In research, mice are often used as models for humans. But there is never any guarantee what happens in a mouse can be replicated in people. And in the case of blood-type compatibility, it has been assumed that by birth, the human immune system had lost the capacity to develop tolerance to antigens from another blood type.

"You read a lot of mouse studies and you say: 'Well, great, but so what?' " West noted.

"So one of the really exciting things is when you can show a direct application between something that can be seen in mice and something that then happens the same way in humans."

One of the children was 14 months old when the operation took place. At that point, the immune system has started to develop antibodies to foreign blood types.

But the transplant seems to have reversed the process - suggesting that if scientists can figure out the mechanisms at work, they might be able to induce tolerance even after the immune system has matured.

"We think there's some malleability in the system," West said. "But we don't know the limits of it yet or how you could push those limits, exactly."

This article posted November 25, 2004.

Researchers show non-Matching transplant induces long-Term blood type tolerance

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