Once a transplant patient gets past the first week to three months with their new organ, the risk of rejection drops substantially—at least for the first year. But over time, the immunosuppressants that keep their body from attacking it stop working as effectively. And if they do work, the medicines’ choke hold on the immune system blinds it to malignant cells, putting patients in danger of developing cancer.
But while these challenges are well-known to the medical community and transplant patients, there has been relatively little progress towards better post-transplant drugs in the past few decades. Now, a study published April 21 in Science Immunology by researchers at the University of Pittsburgh illuminates a new pathway to preventing chronic kidney transplant rejection in mice. They hope their findings will lay the groundwork for a clinical trial.
“In solid organ transplantation, such as kidney transplantation, one-year outcomes are excellent because we have immunosuppressant drugs that manage the problem of acute rejection,” senior co-author Fadi Lakkis, M.D., scientific director of the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh Medical Center, said in a press release. “But over time, these organs often start to fail…understanding this problem was the motivation behind our study.”
Lakkis’ team researches a type of immune cell called a tissue-resident memory T cell, or Trm. Trms are present only in tissues, not in the bloodstream. Back in 2021, the lab showed that these Trms contribute to transplant rejection, setting them up as a potential target for preventing rejection.
The new study builds on that work by revealing how Trms are maintained in transplanted kidneys over time—and how to disrupt their signaling pathways. Using a mouse model of kidney transplantation developed by some members of the team, the researchers showed that Trms had learned to recognize molecules within the donated kidney as foreign and, thus, were constantly being exposed to them. This was facilitated by an inflammatory molecule called IL-15 and another immune cell called a dendritic cell, which presented the antigen and IL-15 to receptors in Trms. Together, the dendritic cells and IL-15 prevent Trms from becoming exhausted, so they endure in the tissue for a long time.
The antigen Trms react to is present throughout the tissue, so it’s impossible to remove it. Instead, the researchers came up with a strategy that worked at the level of the dendritic cells and IL-15. Removing or impairing dendritic cells lowered the number and activity of Trms, as did blocking IL-15 signaling. Further experiments showed that blocking IL-15 with an antibody that kept it from binding to Trms dramatically improved the survival time of transplanted kidneys: 100% of the organs in the six models that received the antibody survived for the 182-day study period, compared to just 10% in the seven controls.
Given that the approach doesn’t require suppressing T cell activity, unlike other immunosuppressant strategies, the researchers think it could be a viable option for preventing graft rejection without opening the body up to complications from prolonged immune dysfunction.
“We have identified actionable targets for clinical translation given that chronic rejection remains a major obstacle to long-term survival of allografts,” the researchers concluded in their paper. “Manipulating these maintenance signals could ablate pathogenic TRM cells that likely underlie chronic pathologies.”