Emory scientists have identified a way to stop troublemaker cells that are linked to immune rejection after kidney transplant. The finding could eventually allow transplant patients to keep their new kidneys for as long as possible, without the side effects that come from some current options for controlling immune rejection.
The results are published in Journal of Clinical Investigation.
The standard drugs used for many years, calcineurin inhibitors, show side effects on cardiovascular health and can even damage the kidneys over time. A newer FDA-approved medication called belatacept, developed in part at Emory, avoids these harmful effects but is less effective at stopping acute rejection immediately after the transplant. Belatacept is a “costimulation blocker” – it interferes with a signal some immune cells (T cells) need to proliferate and become activated.
Researchers led by Emory transplant surgeon Andrew Adams, MD, PhD suspected that long-lasting memory CD8+ T cells were resistant to belatacept’s effects.
“Our previous work identified that memory CD8+ T cells may be elevated in animals and human patients who go on to reject their transplanted organs while taking belatacept,” says Dave Mathews, an MD/PhD student who worked with Adams and is the first author of the paper.
The researchers identified a certain marker, CD122, which was present on memory CD8+ T cells and important for their activity. On T cells, CD122 acts as a receiving dish for two other secreted molecules, IL-2 and IL-15, generally thought of as inflammatory cytokines, or protein messengers that can encourage graft rejection.
IL-2 and IL-15 can get around belatacept’s blockade. They even push T cells into turning down CD28, which is what belatacept interferes with. The current FDA-approved belatacept-based regimen for kidney transplant includes an antibody that blocks IL-2, but not Il-15.
IL-15 specifically encourages memory T cells, whereas IL-2 encourages naïve T cells. Targeting CD122 blocks both IL-2 and IL-15. Thus, going after CD122 might help control immune cells that are still left making mischief after belatacept.
“We have found that immune memory plays an important role in transplant rejection, particularly when patients are being treated with drugs like belatacept,” Adams says.
“We were able to show in mice and then in non-human primates, that blocking CD122 with a new therapeutic antibody, along with costimulation blockade, prolongs transplant survival,” Mathews says.
Even with the combination, transplanted kidneys only lasted 35 to 218 days in the non-human primate experiments, according to the data in the JCI paper. Mathews suggests that higher doses of the anti-CD122 agent may help, but also says that other mechanisms may be responsible for residual immune rejection.
The researchers did not see a re-emergence of dormant viruses, such as cytomegalovirus (CMV), in the immunosuppressed animals. This indicates that the immune system is still functioning well enough to “hold down the fort.” CMV reactivation can have severe effects in immunocompromised patients after transplant.
Looking ahead, inhibition of CD122 has also been tested as an intervention against the autoimmune disease of type 1 diabetes (JCI Insight paper).
The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (F30DK109665), the National Institute for Allergy and Infectious Diseases (AI051731) and by Yerkes National Primate Research Center.
Note: Memory CD8+ T cells are the same cells studied by Emory Vaccine Center director Rafi Ahmed’s lab in context of viral infection and cancer. In 2017, his lab published a study in Science showing that revival of CD8+ T cells by cancer immunotherapy agents is dependent on CD28, the same surface molecule blocked by belatacept.