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.
In the first paper, David Mathews, an MD/PhD student in Adams’ laboratory, designed experiments using a non-human primate model of kidney transplant to test this hypothesis. At Yerkes National Primate Research Center, 24 rhesus macaques underwent kidney transplant and were treated with post-transplant drugs very similar to what human patients receive. Of the 16 animals that received belatacept, 6 displayed signs of immune rejection and eventual graft loss, while 10 did not.
Those that rejected their transplanted kidneys while receiving belatacept tended to have higher levels of certain immune cells before transplant – in particular, CD8+ CD28+ memory T cells. [In 8 animals that received the calcineurin inhibitor regimen, levels of this type of memory T cell did not matter as much for rejection.]
“We think that this population gives rise to immune cells that infiltrate and reject the kidney despite belatacept treatment,” says Mathews, co-first author of the paper along with thoracic surgery fellow Walter Wakwe, MD.
The companion paper by Ford’s group provided similar results from retrospective clinical studies in human transplant recipients. Miriam Cortes, a visiting surgeon from King’s College London, examined the immune cells in patients before they underwent kidney transplant and were treated with belatacept at Emory. The cells that gave hints of future rejection were a similar subset as in the non-human primates, although CD4+ CD28+ memory T cells seemed to be more important in human patients. The authors noted that there are some differences between the primate model and human studies, since humans that undergo transplant tend to be older and have kidney disease, as well as having more immune exposures than juvenile monkeys. Also: a possibly relevant 2016 paper on this topic from Duke.
Cortes and Ford suggest that a test for levels of memory T cells could potentially be used as a pre-transplant screen to determine eligibility for belatacept therapy:
“Because this test can be easily run by any clinical flow cytometry laboratory, it would be widely applicable to help transplant practitioners determine an individual patient’s likelihood of being rejection-free on belatacept.”
The findings by Ford and Adams formed the basis for the recent renewal of a $12.6 million NIH grant to examine strategies to overcome “costimulation-blockade resistant rejection.”
This work was supported by funding from Bristol-Myers Squibb, the American Society of Transplant Surgeons, the National Institute of Allergy and Infectious Diseases (U19AI051731), the National Institute of Diabetes and Digestive and Kidney Diseases (F30DK109665) and the Office of Research Infrastructure Programs (Primate centers: P51OD11132). Authors Ford and Adams have received research funding and consulting fees from Bristol-Myers Squibb. This relationship has been reviewed and is managed by Emory University through its conflict of interest office.