Memory—a key feature of the adaptive immune system—is evident in the innate immune system, too. But it has been unclear whether memory in the innate immune system is specific to previously encountered antigens. Now it appears that antigen-specific memory is in fact an attribute of the innate immune system’s monocytes and macrophages, and not just the adaptive immune system’s T cells and B cells. What’s more, the innate immune memory seems to play a role in the chronic rejection of transplanted organs. If this memory is blocked, a new study suggests, organ transplants could last longer.

The new study, which was led by researchers at the University of Pittsburgh School of Medicine and Houston Methodist Hospital, used a genetically modified mouse organ transplant model to show that the innate immune cells, once exposed to a foreign tissue, could remember and initiate an immune response if exposed to that foreign tissue in the future. Detailed findings from the study appeared in Science, in an article titled, “PIRs mediate innate myeloid cell memory to nonself MHC molecules.”

“Here, we show that murine monocytes and macrophages acquire memory specific to MHC-I antigens and identify paired immunoglobulin-like receptors-A (PIR-A) as the MHC-I receptors necessary for the memory response,” the article’s authors wrote. “We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection.”

Image of transplanted mouse kidney tissues showing recipient immune cells (blue) in normal (left) but not genetically modified mice (right). [Image adapted from Dai H et al., Science 2020; 10.1126/science.aax4040]

These findings suggest that drugs could be developed to lengthen the long-term survival of transplanted organs. That is, drugs could target elements of the MHC-I allorecognition pathway that is mediated by monocytes and macrophages, preventing chronic rejection, the leading cause of transplant failure.

The problem of chronic rejection has bedeviled the field of organ transplantation, which has had to rely on immunosuppressive drugs. Although these drugs have made organ transplantation a reality, they have serious side effects and often fail to stave off rejection over the long term.

Immunological memory—which was thought to be unique to the adaptive immune system’s ability to recognize and attack foreign pathogens—is also why transplanted organs are eventually rejected, even in the presence of immune-suppressing drugs.

This image shows graft survival rates for kidney transplants in 1985 and 2016. Medical advances have helped dramatically lower the rates of acute rejection (within the first year) after transplant, but chronic rejection continues to reduce long-term organ survival. [Fadi Lakkis, University of Pittsburgh, data adapted from United States Renal Data System]

“The rate of acute rejection within one year after a transplant has decreased significantly, but many people who get an organ transplant are likely to need a second one in their lifetime due to chronic rejection,” said Fadi G. Lakkis, MD, senior author of the current study and scientific director of the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh. “The missing link in the field of organ transplantation is a specific way to prevent rejection, and this finding moves us one step closer to that goal.”

“Innate immune cells, such as monocytes and macrophages, have never been thought to have memory,” added Martin H. Oberbarnscheidt, MD, PhD, a co-senior author and assistant professor of surgery at the University of Pittsburgh. “We found that their capacity to remember foreign tissues is as specific as adaptive immune cells, such as T cells, which is incredible.”

The researchers then used molecular and genetic analyses to show that PIR-A was required for this recognition and memory feature of the innate immune cells in the hosts. When PIR-A was either blocked with a synthetically engineered protein or genetically removed from the host animal, the memory response was eliminated, allowing transplanted tissues to survive for much longer.

“Knowing exactly how the innate immune system plays a role opens the door to developing very specific drugs, which allows us to move away from broadly immunosuppressive drugs that have significant side effects,” noted Lakkis.

The finding has implications beyond transplantation, according to Oberbarnscheidt: “A broad range of diseases, including cancer and autoimmune conditions, could benefit from this insight. It changes the way we think about the innate immune system.”

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