Artificial foreign blood group implants may give children a better shot at later ‘mismatched’ heart transplants

Lori West

Pediatric cardiologist Dr. Lori West made medical history 12 years ago when her team successfully transplanted a heart from a donor with an incompatible blood type into a three-week-old infant.

The life-saving surgery violated a cardinal rule that patient and donor blood types must be compatible. And it proved her hunch that an infant’s immune system is too underdeveloped to recognize foreign blood antigens and create antibodies to fight them.

West is taking her discovery to a whole new level with a $2-million Canadian Institutes of Health Research (CIHR) emerging team research grant. The grant will allow her and a high-level multidisciplinary team to try to find a way to artificially manipulate neonatal immune systems, so that heart transplants with incompatible blood donors can be performed later in life. 
 
“This would prepare infants who may have serious congenital heart diseases or malformed hearts for eventual transplant,” says West, who is the director of the Heart Transplant Research Program and a professor in the Departments of Pediatrics, Surgery and Immunology at the U of A. “If you can change their antibody response in the neonatal period, then they may be able to accept donor hearts of other blood groups later, which expands the available pool of scarce donor organs.”

West received a $1.2-million, five-year research funding commitment from the Women and Children’s Health Research Institute after being recruited by the University of Alberta from the Toronto Hospital for Sick Children in 2005. She also received a 2009 WCHRI Internal Grant to develop and evaluate an online support system for parents of children who have had heart transplants at the Stollery Children’s Hospital. The award was funded by the Stollery Children’s Hospital Foundation.

When West was appointed director of the fledgling heart transplant program at Sick Kids in 1994, she saw more than half of the babies on the transplant waiting list die before a heart of suitable size and compatible blood type could be found. The wrong blood type was most often the reason scarce donor hearts were turned down.

Research that she had done years earlier at Oxford University made her wonder whether ABO blood group mismatched hearts could be successfully implanted into infants. Such a procedure would be fatal in adults, whose blood group antibodies would immediately recognize and reject the incompatible donor heart as a foreign substance.

West’s experiments at Oxford were based on the work of British scientist Sir Peter Medawar who won a Nobel prize in 1960 for his pioneering work in immunology. Medawar injected cells from unrelated strains of mice into newborn mice. He was able to successfully perform skin grafts from the same unrelated donors on the recipient mice when they matured. In her study, West transplanted hearts, instead of skin, into mice that had been injected with foreign cells at birth and got similar results.

Her findings had huge potential implications for human babies who are also born with underdeveloped immune systems. They suggested that ABO-mismatched transplants might be safe in infants. By 1996, West was ready to make the experimental leap rather than face the prospect of losing yet another young patient. A Winnipeg couple was also willing to have the unproven procedure tried on their infant son as a last-ditch effort to save his life. Braving the scepticism of her colleagues, West oversaw the transplant of a type AB heart into three-week-old Caleb Schroeder, an O blood type, and revolutionized the field of pediatric heart transplantation.

‘Mismatched’ pediatric heart transplants are now performed in 18 transplant centres in Canada, the U.S. and Europe, including the Stollery Children’s Hospital, which performed the highest number of pediatric heart transplants in Canada in 2008. The long-term prognosis appears positive as the babies who received the first transplants have grown up and thrived.

“We were able to show that this is a safe procedure,” says West. “It offered new hope for children who had virtually no other options. But we didn’t know what the immune response to the mismatched blood type would be over time.”

Time has shown that as the children have matured, their immune systems continue to tolerate different blood group antigens. Their bodies don’t attack different blood group antigens from their own. “We now know that if you want change the immune system, you have to intervene early in life,” says West. “By introducing those antigens artificially in an implant of some sort, we’re hoping to induce a similar tolerance, so that O blood group patients, for example, could be tolerized to A and B blood groups during infancy. Then when they’re five years old they may still be suitable to receive a mismatched transplant.”

During the next five years, West is heading a multi-disciplinary team whose first challenge is to chemically recreate the different blood group antigens, and then to link them to tiny implantable devices. The tiny implants will be inserted into young mice, in body areas such as the peritoneal cavity that generate blood type immune system reactions. The idea is to find ways to selectively turn off the blood type immune response in immature immune systems without causing harm. If this can be successfully done in humans, then incompatible blood type heart transplants could be performed on children at a later age.  

The team includes Dr. Todd Lowary, Dr. Jillian Buriak and Dr. Chris Cairo from the U of A’s Department of Chemistry and Dr. David Cramb from the U of C’s Department of Chemistry. Lowary is also a carbohydrate chemist with the Alberta Ingenuity Centre of Carbohydrate Chemistry and Buriak is also a senior researcher with the National Institute of Nanotechnology.

“The exciting thing is that the team grant is pulling together biological scientists like myself with chemists and nanotechnologists, people who normally have not worked together, to construct something that will be an effective tool down the road,” says West.

For information on the West Research Group, go to www.cardiactransplantresearch.med.ualberta.ca