Cdn study pinpoints genes that predict bone marrow 'dangerous donors'

Canadian researchers believe they have come up with a way to predict whether transplants from specific bone marrow donors are likely to trigger rejection an advance that could help doctors weed out so-called "dangerous donors" and cut back on immune suppressant drugs for some transplant recipients.

If corroborated, their findings could lower the risk of graft-versus-host disease for bone marrow recipients. They could eventually also help predict which recipients will reject transplanted kidneys, livers and other solid organs, allowing doctors to tailor post-transplant drug regimes according to the recipient's risk.

"I think it would become a routine test," senior author Dr. Claude Perreault said Monday of the finding's applicability for bone marrow transplants. "It would be easy and cheap."

The study was published in Tuesday'sissue of the journal Public Library of Science Medicine.

The thinking on transplants has been that when a person gets a solid organ transplant a donated kidney or a portion of a liver the recipient's immune system must be suppressed for life in order to ensure that it does not turn against and destroy what it would see as a foreign organ.

With bone marrow, doctors are essentially transplanting the donor's immune system produced in the marrow into the recipient. And it is that donated immune system that turns against the recipient. If that process is not checked by immune suppressing drugs, potentially fatal graft-versus-host disease develops.

However, early attempts to transplant bone marrow showed that about 25 per cent of recipients didn't develop graft-versus-host disease, even though they were not put on a regime of immunosuppressant drugs.

Rejection clue

Perreault, with the Institute of Research in Immunology and Cancer at the University of Montreal,and his colleagues tried to figure out if following that clue could lead them to a way to differentiate which donors were likely to induce graft-versus-host diseaseand which weren't.

Dr. Fred Appelbaum, director of the clinical research division of the Fred Hutchinson Cancer Research Center in Seattle, Wash., said a variety of researchers had been trying to puzzle out why, even among well-matched donors and recipients, the risk of graft-versus-host disease varies.

"His [Perreault's] approach was to try and figure out: Is there a way that we can do a global assessment, that we take into account all the genes and their impact on cells?" said Appelbaum, who was not involved in this study.

Immune patterns

The Montreal team analyzed the workings of 19,000 genes from 50 bone marrow donors, looking for discernible patterns of over- or under-production of important immune system proteins. They found that by looking at the activities of 17 genes, they could identify dangerous and non-dangerous donors.

Perreault said the group will now test the theory in a larger group of donors, to see if their tool really works. The gene activities of several hundred donors will be studied for this follow-up research.

Appelbaum said if corroborated, the work will provide an important predictive tool for doctors planning bone marrow transplants and treating recipients after the procedure.

"In those cases where you have multiple donors, you could use it to select one donor over another," he said. "In those cases where you don't have that option you might be able to use it to fine tune the amount of immune suppression you give [recipients]."

"So that if someone is a dangerous donor, you'd use higher doses of post-transplant immune suppression and if someone appears to be a safe donor, you might be able to more rapidly taper the immune suppression so that they're at less risk of development of infections and other complications."

And if the solid organ rejection can be predicted in the same manner, in the future, recipients of donated livers and kidneys would be tested to see whether they are likely to reject, and their drug regimes would be set accordingly.

The research was funded by Genome Quebec, Genome Canada, the Dana Foundation and the Health Research Fund of Quebec.