“In solid organ transplants like kidney transplants, one-year results are excellent because we have them
“Managing the challenge of acute rejection,” said senior author Fadi Lakkis, MD, distinguished professor of surgery, professor of immunology and medicine, and scientific director of the Thomas E. Starzl Transplant Institute at Pitt and UPMC. “However, over time, these organs often begin to fail due to a slower form of rejection called chronic rejection, and existing drugs do not help. Understanding this problem was the motivation for our study.”
Previously, Lakkis and his colleagues showed that a type of immune cell called tissue-resident memory T cells induces chronic rejection. Like all memory T cells, these resident versions “remember” threats they have previously encountered by recognizing specific identifying features called antigens. But unlike memory T cells that circulate in the blood, tissue-resident memory T cells reside in organs.
Transplant rejection: New insights
In the new study, first author Roger Tieu, Ph.D., a student in the Medical Science Education Program at Pitt, discovered two factors that maintain permanent memory T cells over time in kidney transplants. The first is the antigen itself – the molecules that T cells use to recognize the donor graft as foreign. Because resident T-cells reside within the kidney graft, they are constantly exposed to such antigens. The second factor is a cytokine or inflammatory signaling protein called IL-15.
Key to this process is another type of immune cell called dendritic cells, which captures both antigen and IL-15 and presents them to receptors on resident memory T cells.
“Dendritic cells are like the conductor of an orchestra,” Lakkis said. “They are important for activating many types of immune cells and coordinating immune responses.”
When researchers depleted dendritic cells or blocked their ability to present antigen or IL-15, they saw a decrease in the amount and functionality of persistent memory T cells.
“Antigen and IL-15 are required for T cell maintenance,” said co-lead author Martin Oberbarnscheidt, MD, Ph.D., assistant professor of surgery at Pitt. “If you remove both, the number of permanent memory cells decreases. It’s impossible to pick up the antigen in a transplant patient because it’s found throughout the donor organ, but targeting IL-15 is clinically translatable.”
Indeed, when the researchers blocked IL-15 signaling with an antibody that prevented IL-15 from binding to its receptor on T cells, they found that graft survival was significantly prolonged in mouse kidney recipients.
“I had the privilege of working with transplant patients in my medical school,” Tieu said. “I am excited that our work has the potential to transform from the laboratory to the clinic with the goal of reducing chronic rejection and improving the quality of life for our patients.”