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Troublemaker cells predict immune rejection after kidney transplant

Evidence is accumulating that the presence of certain "troublemaker" memory T cells can predict the likelihood of belatacept-resistant immune Read more

Mandy Ford

Troublemaker cells predict immune rejection after kidney transplant

Emory scientists have identified troublemaker cells—present in some patients before kidney transplantation—that are linked to immune rejection after transplant. Their results could guide transplant specialists in the future by helping to determine which drug regimens would be best for different groups of patients. Eventually, the findings could lead to new treatments that improve short- and long-term outcomes.

Transplant patients used to have no choice but to take non-specific drugs to prevent immune rejection of their new kidneys. While these drugs, called calcineurin inhibitors, are effective at preventing early rejection, they lack specificity for the immune system and ironically can damage the very kidneys they are intended to protect. In addition, their side effects lead to higher rates of high blood pressure, diabetes, and cardiovascular disease, ultimately shortening the life of the transplant recipient. This changed with the advent of costimulation blockers, which avoid these harmful side effects. Emory transplant surgeons Chris Larsen and Tom Pearson, together with Bristol-Myers Squibb, helped develop one of these new drugs called belatacept, which blocks signals through the costimulatory receptor CD28.

In a long-term clinical study of belatacept, kidney transplant patients tended to live longer with better transplant function when taking belatacept compared with calcineurin inhibitors. Despite these desirable outcomes, acute rejection rates were higher in patients treated with belatacept.

Andrew Adams, an Emory transplant surgeon who focuses on costimulation blockade research, notes: “While the acute rejection seen with belatacept is treatable with stronger immunosuppression, there may be long-term effects that linger and impair late outcomes.”

Most transplant centers have not yet adopted this new therapy as their standard of care because of the higher rejection rate as well as other logistical concerns, thus limiting patients’ access to potential health benefits afforded with belatacept treatment.

Adams and colleague Mandy Ford have identified certain types of memory T cells, which typically provide long-lasting immunity to infection, as potential mischief-makers in the setting of organ transplants treated with belatacept. Evidence is accumulating that the presence of certain memory T cells can predict the likelihood of “belatacept-resistant” rejection. Two recent papers in American Journal of Transplantation by Ford and Adams support this idea. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Are you experienced?

Are you experienced? Your immune system undoubtedly is. Because of vaccinations and infections, we accumulate memory T cells, which embody the ability of the immune system to respond quickly and effectively to bacteria or viruses it has seen before.

Not so with mice kept in clean laboratory facilities. Emory scientists think this difference could help explain why many treatments for sepsis that work well in mice haven’t in human clinical trials.

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Mandy Ford has teamed up with Craig Coopersmith to investigate sepsis, a relatively new field for her, and the collaboration has blossomed in several directions

“This is an issue we’ve been aware of in transplant immunology for a long time,” says Mandy Ford, scientific director of Emory Transplant Center. “Real life humans have more memory T cells than the mice that we usually study.”

Sepsis is like a storm moving through the immune system. Scientists studying sepsis think that it has a hyper-inflammatory phase, when the storm is coming through, and a period of impaired immune function afterwards. The ensuring paralysis leaves patients unable to fight off secondary infections.

In late-stage sepsis patients, dormant viruses that the immune system usually keeps under control, such as Epstein-Barr virus and cytomegalovirus, emerge from hiding. The situation looks a lot like that in kidney transplant patients, who are taking drugs to prevent immune rejection of their new organ, Ford says.

Ford’s team recently found that sepsis preferentially depletes some types of memory T cells in mice. Because T cells usually keep latent viruses in check, this may explain why the viruses are reactivated after sepsis, she says. Read more

Posted on by Quinn Eastman in Immunology Leave a comment