Immune Cell Drives Chronic Transplant Rejection in Mice, Suggesting Therapeutic Target

University of Pittsburgh (Pitt) researchers identified a type of immune cell that drives chronic organ transplant failure in a mouse model of kidney transplantation. Their study uncovered pathways that could feasibly be targeted therapeutically to improve patient outcomes, and they suggest their findings could be translated from lab to clinic, with the goal of mitigating chronic rejection and elevating quality of life for patients.

“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, MD, 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.”

Lakkis, together with first author Roger Tieu, PhD, medical scientist training program student at Pitt, and colleagues described their findings in a paper titled, “Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15.”

Organ transplantation is a life-saving treatment for patients with end-stage organ disease, the authors explained. “However, chronic rejection remains a barrier to long-term allograft survival.” CD8 T cells play a key role in graft failure, and Lakkis and his colleagues had previously shown that a type of immune cell called tissue-resident memory T cells (TRM) drive chronic rejection. “We have previously shown that TRM cells form in murine kidney allografts and mediate chronic rejection,” they wrote in their newly released paper. Like all memory T cells, these resident versions “remember” previously encountered threats by recognizing specific identifying features called antigens. But unlike most memory T cells, which circulate in the bloodstream, tissue-resident memory T cells live within organs. “TRM cells are a noncirculating, long-lived population with the potential to mount rapid, in situ immune responses by coordinating both local innate and adaptive immune cells,” the team noted. “However, it is unclear what factors are responsible for the long-term maintenance of TRM cells in kidney allografts.”

Fadi Lakkis, MD, distinguished professor of surgery, professor of immunology and medicine, and scientific director of the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh and UPMC [UPMC]

Through their newly reported study in mice, Lakkis, Tieu, and colleagues discovered two factors that maintain resident memory T cells in kidney grafts over time. The first is the antigen itself—the molecules that T cells use to recognize the donor graft as foreign. Because resident T cells remain within the kidney graft, they are constantly exposed to such antigens. The second factor is the cytokine IL-15. This interleukin, the team noted, is “a cytokine crucial for the maintenance of memory CD8 T cells, including TRM cells in the native kidney during homeostasis (i.e., noninflamed conditions).”

The overall rejection in kidney transplant recipients, the newly reported study noted, also involves the immune system’s dendritic cells (DCs) which capture both the antigen and IL-15 and present them to receptors on resident memory T cells. “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.” When the researchers depleted dendritic cells or blocked their ability to present antigen or IL-15, there was a drop in resident memory T cell quantity and functionality. “Antigen and IL-15 are required for T cell maintenance,” said co-senior author Martin Oberbarnscheidt, MD, PhD, 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.”

Their study confirmed that using an antibody to block IL-15 signaling resulted in greatly prolonged graft survival in mouse kidney recipients. “We demonstrate that blocking IL-15 from binding to its receptor on T cells prevents chronic rejection and prolongs allograft survival,” they wrote. “We found that cognate antigen and IL-15 play important nonredundant roles in the maintenance and functionality of TRM cells. Both were required. Presentation of antigen and IL-15 were mediated by intragraft DCs, and ablation of DCs led to disruption of TRM cell maintenance.”

Martin Oberbarnscheidt, MD, PhD, assistant professor of surgery at the University of Pittsburgh [Martin Oberbarnscheidt, MD, PhD]

The researchers hope that the findings could lead to future clinical trials to test the antibody in transplant patients to minimize chronic rejection. Blocking IL-15 signaling could enable more precise targeting of resident memory T cells within the graft, while minimizing global immunosuppression of other T cells throughout the body that are important for immunity to infections.

Noting limitations of their study, the team concluded, “… we have identified actionable targets for clinical translation given that chronic rejection remains a major obstacle to long-term survival of allografts. Manipulating these maintenance signals could ablate pathogenic TRM cells that likely underlie chronic pathologies.”

“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.”