Identifying the molecular culprits behind organ rejection

Investigators have revealed more about how the immune system regulates organ rejection in mice, findings which may prove useful for improving transplant tolerance in humans, according to a recent study published in the Journal of Clinical Investigation.

More than 42,000 organ transplants were performed in 2022, but roughly 10-15 percent of transplant recipients will experience symptoms of organ rejection. Even if organs are initially accepted, secondary infections can induce inflammation, triggering rejection later.

“Many patients who receive a lifesaving organ transplant still experience bouts of rejection later, sometimes after infections,” said Maria-Luisa Alegre, MD, PhD, Professor of Medicine at the University of Chicago, and co-senior author of the new study. “We wanted to understand which immune cells were responsible for transplant rejection after infection and devise a strategy to inactivate those T cells early after transplantation. This study provides a new pathway toward making organ transplants more resilient.”

The study was a collaborative effort including Anita Chong, PhD, Professor of Surgery at UChicago, and Zheng Zhang, MD, Research Professor of Surgery in the Division of Organ Transplantation at Northwestern University. The researchers first analyzed how T-cells reacted following a heart transplant in mice. Some of these mice were treated with an immunomodulating regimen that consisted of donor spleen cells followed by a T-cell targeted protein, anti-CD154, known to induce transplant acceptance.

Cells display proteins called antigens, which our immune system uses to decide if cells and molecules are from the self or from another organism, like a pathogen or donated organ. The two major types of antigens expressed in donor organs are called MHC class I and MHC class II. Using two different T-cell “tracers” that recognize antigens in the donor organ, the researchers investigated the immune response in transplant recipient mice that tolerated their donor grafts. One type of T cells (TCR75) that recognize a donor MHC class I-derived antigen exhibited signs of exhaustion, while another type of T cells (TEa) that recognize a donor MHC class II-derived antigen remained functional.

Next, scientists infected mice at 30 days post-transplantation with listeria bacteria, which is known to lead to organ rejection. At eight days post-infection, investigators analyzed the endothelial cells of the donor organ and found that those from infected mice upregulated MHC class II levels when compared to uninfected tolerant mice, resulting in activation of TEa cells and rejection.

Investigators hypothesized that exposing the recipient to all donor antigens over a long period of time after transplantation, including to the antigens that are otherwise transient in the graft, could desensitize the host’s TEa cells, lessening the likelihood of rejection.

To test this, investigators treated mice with anti-CD154 and administered either a single dose of donor spleen cells or administered several over the course of a month. They then analyzed the TEa cells of the mice and found that only the repeated injections induced exhaustion in the TEa cells.

At 35 days after heart transplantation, the graft-tolerant mice were infected with listeria. Mice that had been given multiple donor spleen cell injections showed fewer signs of rejection and had less inflammation and tissue damage than mice only given one, according to the study.

The findings suggest that exposing T-cells of transplant recipients to repeated injections of antigens from their organ donor under cover of an immunomodulating therapy such as anti-CD154 may help the recipient’s body avoid organ rejection following infection. The results of the study also identify donor MHC class II as a problematic antigen that may be a cause of rejection after severe infections, said Zhang.

"When we infected transplanted mice with listeria, we found that the expression of donor MHC class II increased dramatically in the graft, a consequence of the cytokine release and inflammation caused by the infection, with several detrimental effects contributing to a rejection response,” Zhang said. “But repeated infusions of donor antigen, under cover of anti-CD154, can enhance tolerance. And this paper suggests that the duration of expression of the different donor antigens in the graft can influence how stable that tolerance is.”

Moving forward, the team hopes to study the mechanisms underlying transplant tolerance and the inflammatory events that make tolerance vulnerable. By understanding these mechanisms, they can help find ways to make organ transplants more resilient following infections.

The study, “Heterogeneity in allospecific T cell function in transplant tolerant hosts determines susceptibility to rejection following infection,” was supported by National Institute of Allergy and Infectious Diseases (NIAID) grant P01AI-97113 to Maria-Luisa Alegre and Anita Chong. Additional authors include Christine M. McIntosh, Jennifer B. Allocco, Peter Wang, Michelle L. McKeague, Alexandra Cassano, Ying Wang, Stephen Z. Xie, Grace Hynes, Ricardo Mora-Cartín, Domenic Abbondanza, Luqiu Chen, Husain Sattar, and Dengping Yin from UChicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID.

Adapted from a press release by Northwestern University.