Treatment for Chronic Transplant Rejection

In a mouse model of kidney transplantation, the University of Pittsburgh researchers identified a type of immune cell that drives chronic transplant rejection and discovered pathways that could be therapeutically addressed to enhance patient outcomes. The findings have been published in the journal 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 transplant rejection, and current medications don’t seem to help. Understanding this problem was the motivation behind our study.”

Previously, Lakkis and colleagues demonstrated that chronic rejection is driven by a kind of immune cell known as tissue-resident memory T cells. These resident T cells, like other memory T cells, “remember” previously encountered dangers by recognizing certain identifying traits known as antigens. Tissue-resident memory T cells, in contrast to most memory T cells, which circulate in the bloodstream, live within organs.

First author Roger Tieu, Ph.D., a Medical Scientist Training Program student at Pitt, uncovered two characteristics that keep resident memory T cells in kidney grafts alive over time in the new study. The first is the antigen itself, which is the chemicals used by T cells to detect the donor graft as alien. Because resident T cells live within the kidney graft, they are constantly exposed to antigens of this type.

The second component is IL-15, a cytokine or inflammatory signaling protein.

Dendritic cells, which catch both the antigen and IL-15 and transfer them to receptors on resident memory T cells, are also important in 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.”

When the researchers depleted dendritic cells or blocked their ability to present antigen or IL-15, they saw 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, 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.”

Indeed, when the researchers blocked IL-15 signaling with an antibody that prevented IL-15 from attaching to its receptor on T cells, they discovered that graft survival in mice kidney recipients was considerably prolonged.

The researchers anticipate that their findings may pave the way for clinical studies to test the antibody in transplant recipients in order to reduce chronic rejection. By inhibiting IL-15 signaling, researchers may be able to more precisely target resident memory T cells within the graft while limiting widespread immunosuppression of other T cells throughout the body that is critical for infection immunity.

“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 the quality of life for our patients.”

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