Over time, it’s common for the body’s immune system to slowly and persistently degrade a transplanted kidney. The result is loss of function and, in the worst case, rejection. Up to one-third of kidney recipients lose the organ within ten years after transplantation. Unfortunately, early biomarkers of kidney transplant rejection are lacking. But scientists at the University of Pittsburgh School of Medicine have discovered one that signals pending kidney rejection up to eight months ahead.
Further, their discovery suggested that treatment with anti-tumor necrosis factor (TNF) drugs might re-set the organ’s pathology and lead to a longer functional life.
“We can’t tell a priori if a patient is on too much or too little immune suppression—we don’t know until after rejection or an infection has already started,” said senior author David Rothstein, M.D., the Pittsburgh Steelers chair in transplantation and professor of surgery, medicine and immunology at Pitt. “We wanted to find something that would tell us this patient is at risk of rejecting later so that we could change their immunosuppressants up front before the immune system revs up, before scarring and chronic damage is done.”
The research team studied blood samples from 319 patients who had received kidney transplants at two medical centers – one in the U.S., the other in England. They identified that the ratio of IL-10 and TNF was useful for predicting those at high-risk of kidney rejection. In their study, 91% of the patients classified as high-risk by this biomarker ratio went on to reject the kidney within the first year post-transplantation. Only 10% of patients in a low-risk group rejected the organ. They also observed that people in the high-risk group were significantly more likely to lose their transplanted kidneys five years after the surgery.
The ratio of IL-10 and TNF serves as a functional biomarker. Both of these molecules are secreted by regulatory B cells, a subset of B cells that have an active role in promoting or suppressing immune responses. Recent studies suggest that regulatory B cells have an active role in organ rejection. Measuring the balance between IL-10 and TNF gave researchers an indication of the health of these regulatory B cells and predicted which transplant recipients were at higher-risk of kidney rejection.
“Being a functional biomarker, ours gives us an idea of what goes wrong in these high-risk patients,” Rothstein said. “The balance between IL-10 and TNF seems to indicate your immune setpoint—is your immune system going to be quiescent or is it going to be revved up and try to reject the transplant? We hope we can restore that balance with anti-TNF drugs.”
Although Anti-TNF drugs like infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), do not currently have a major role in transplantation, they are commonly used in certain autoimmune disease, like rheumatoid arthritis, inflammatory bowel disease and other conditions marked by inflammation.
To see what effect anti-TNF therapy might have, the researchers mixed an anti-TNF drug with B cells taken from high-risk patients. They observed changes in the ratio of IL-10/TNF as well as other changes that suggested restoration of regulatory B cell activity.
The goal with anti-TNF treatment would be to restore a healthy immune system balance before rejection has a chance to begin or progress. Human clinical studies are essential to test the hypothesis.