In a mouse model of kidney transplantation, researchers from the University of Pittsburgh have identified a specific immune cell type that contributes to chronic organ transplant failure and discovered pathways that may be therapeutically addressed to enhance patient outcomes. The results are presented in a recent study in Science Immunology.
“In solid organ transplantation, such as kidney transplants, one-year outcomes are excellent because we have immunosuppressant drugs that manage the problem of acute rejection,” said co-senior author Fadi Lakkis, M.D., distinguished professor of surgery, professor of immunology and medicine, and scientific director of the Thomas E. Starzl Transplantation Institute at Pitt and UPMC.
“But over time, these organs often start to fail because of a slower form of rejection called chronic rejection, and current medications don’t seem to help. Understanding this problem was the motivation behind our study.”
In the past, Lakkis and his associates have demonstrated how tissue-resident memory T cells, a subset of immune cells, are responsible for chronic rejection. These resident T cells, like other memory T cells, “remember” previously encountered threats by identifying particular distinguishing characteristics called antigens. Tissue-resident memory T cells, however, reside within organs as opposed to the majority of memory T cells, which circulate in the blood.
First author and Medical Scientist Training Programme student at Pitt Roger Tieu, Ph.D., identified two elements that sustain resident memory T cells in kidney grafts throughout time. The initial factor is the antigen itself, which are the chemicals used by T cells to identify the donor graft as being foreign. Residents T cells are always exposed to such antigens since they live inside the kidney graft.
Dendritic cells, a different class of immune cell that captures both the antigen and IL-15 and presents them to receptors on resident memory T cells, are also essential to this process.
“Dendritic cells are like the conductor of the orchestra,” said Lakkis. “They’re critical for activating many types of immune cells and coordinating immune responses.”
Researchers observed a decrease in resident memory T cell quantity and functionality when dendritic cells were reduced or prevented from presenting antigen or IL-15.
“Antigen and IL-15 are required for T cell maintenance,” said co-senior author Martin Oberbarnscheidt, M.D., Ph.D., assistant professor of surgery at Pitt. “If you remove either, resident memory cells decline in number. In a transplant patient, it’s not feasible to take the antigen away because it’s found throughout the donor organ, but targeting IL-15 is clinically translatable.”
In fact, they discovered that the graft survival in mice kidney recipients was significantly increased when the researchers blocked IL-15 signalling with an antibody that prevented IL-15 from binding to its receptor on T cells.
The findings, in the researchers’ opinion, may pave the way for clinical studies to test the antibody in transplant recipients in an effort to reduce chronic rejection. By preventing IL-15 signalling, resident memory T cells in the graft may be targeted more precisely while the overall immunosuppression of other T cells, which are crucial for infection immunity throughout the body, is reduced.
“In my medical school training, I have had the privilege of working with transplant patients,” said Tieu. “I am excited that our work has the potential to be translated from lab to clinic, with the goal of mitigating chronic rejection and elevating quality of life for our patients.”
