Immune traits may identify lucky kidney-transplant recipients

Tests find a genetic signature that may delineate people who could drop immune-suppression therapy

Certain immune-system characteristics may explain why some kidney-transplant recipients can stop taking immune-suppressing drugs without rejecting their new organs, two new studies show.

Doctors might someday use these biological traits — specifically a genetic “signature” found in these unusual patients — to discern which kidney recipients might be able to get off these harsh drugs. But that day hasn’t arrived yet, the scientists caution. 

The two reports, published online May 24, will appear in the June 1 Journal of Clinical Investigation. A third report in the same issue identifies other genetic signatures that may be useful for identifying those kidney recipients most likely to undergo transplant failure. The findings might help doctors determine optimal treatment, says study coauthor Philip Halloran, a nephrologist at the University of Alberta in Canada.

More than half of kidney transplants from deceased donors fail within 10 years, requiring the recipient to go on dialysis or get another transplant, says Peter Heeger, a nephrologist at Mount Sinai School of Medicine in New York City. The loss can stem from rejection, a return of the original kidney disease, the effect of suppression drugs or other factors. The new studies suggest the possibility of using genetics and other biomarkers to predict transplant failure or success, Heeger says. “The goal for these molecular tests will now be to refine them and make them useful in the clinic.”

In the first two studies, scientists identified 60 kidney recipients who had quit their immune-suppressing medication. Most of the patients had received kidneys from living donors, but not all. Patients who quit taking suppression drugs nearly always encounter immune rejection, which results in damage to the kidney, loss of blood filtration capability and kidney failure, says physician and immunologist Maria Hernandez-Fuentes of King’s College London, who was a coauthor of both papers. But these 60 people were able to tolerate a transplant even after quitting immune suppression.

Blood tests comparing these people with patients who remained on immune suppression and healthy controls showed that the naturally tolerant recipients make more B cells — a kind of immune cell that produces antibodies — and are more likely to have activated versions of three genes on their B cells. Nearly all these tolerant people were devoid of any antibodies specifically aimed at the donated kidney.

Although this genetic signature and the immune differences could differentiate some tolerant transplant recipients from the others, they don’t explain the mechanism by which these people can manage without immune-suppressing drugs, Hernandez-Fuentes says. What’s more, it’s not clear whether people are born with this favorable genetic signature and other traits, or if they acquire them somehow, says immunologist Vicki Seyfert-Margolis of the U.S. Food and Drug Administration in Silver Spring, Md., who worked on these studies while at the Immune Tolerance Network in Bethesda, Md.

B cells and the antibodies they make play a role in causing rejection. But in these tolerant patients, some B cells might actually tone down rejection. “One possibility is that the B cells we’re seeing are a kind of regulatory B cell,” says study coauthor Kenneth Newell, a transplant surgeon at Emory University in Atlanta.

The researchers plan to test kidney recipients who are doing well on immune-suppression drugs to see which ones have the seemingly favorable genetic signature. “They supposedly would be amenable to weaning” from antirejection drugs, Hernandez-Fuentes says. But taking people off drugs would require close medical supervision. “We don’t want people trying this on their own,” she warns.

In the other study, Halloran and a team of researchers used kidney biopsies of transplant recipients to assess rejection risk. Using these tissue samples, the scientists used genetic analyses to develop a risk-scoring formula based on features found to predict transplant failure.

Based on this scoring system, the scientists assigned a high or low risk to 105 kidney recipients. Of 52 patients with high-risk scores, 25 had their transplants fail during the follow-up years. Of 53 patients with lower scores, only five failed.

The genes most closely predicting graft failure were ones that are typically switched on in injury repair, suggesting the kidney was struggling to heal itself, he says. Halloran and his team are now checking the predictive ability of the scoring formula in other biopsies.

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