A tiny population of T-cells could serve as a much-needed biomarker—and a potential therapeutic target—for pediatric acute liver failure, according to new research from Children’s Hospital Los Angeles.
The study, led by surgeon-scientist Juliet Emamaullee, MD, PhD, found that T-cells expressing a molecule called programmed cell death protein 1 (PD-1) were present only in the biopsies of children who recovered from acute liver failure without needing a liver transplant.
The findings were presented in a plenary session at the 2023 International Congress of the International Liver Transplantation Society, held May 3-6 in Rotterdam, Netherlands. First author Brittany Rocque, MD, MSc, a general surgery resident in Dr. Emamaullee’s lab, presented the research.
The team will also present the study findings in a plenary session on June 5 at the American Transplant Congress in San Diego.
“It’s an exciting discovery because this is something you could look for in a liver biopsy that could potentially give you valuable information about which children are more likely to need a liver transplant,” explains Dr. Emamaullee, a surgeon and Research Director in the Division of Abdominal Organ Transplantation at CHLA. “But it also opens up a possible treatment pathway.”
Pinpointing single cells
Pediatric acute liver failure is a rapidly progressing and potentially life-threatening illness that affects otherwise healthy children. The condition comes on with few warning signs before a child presents in the emergency room.
Approximately 10% to 15% of patients will end up undergoing a liver transplant. However, many children recover without the need for a transplant and the resulting lifetime of immunosuppression medications. But without reliable predictors of a patient’s trajectory, it can be challenging for physicians to decide when they should move forward with a transplant, and when they should wait.
In search of biomarkers that could help guide these decisions, Dr. Emamaullee and her team conducted a retrospective study examining liver biopsies from 27 children with acute liver failure. Eleven of those children received a liver transplant; 16 of them recovered without a transplant.
The researchers used a technology called imaging mass cytometry to uncover individual immune cells present in each biopsy. The technology produces images that allow researchers to examine up to 40 different proteins in a single cell, all at the same time, from a small section of tissue.
Although imaging mass cytometry is more common in cancer research, the Children’s Hospital Los Angeles team is the only group in the world using it to investigate immune cells in this way. The team has also developed advanced computational biology techniques that turn the images from the technology into a single-cell dataset.
After identifying more than 83,000 immune cells from the biopsies, the investigators discovered the small population of T-cells expressing PD-1. The cells were found only in patients who had recovered without a transplant.
“These cells are relatively rare; they’re less than 1% of the cells that we see in the biopsy,” Dr. Emamaullee says. “It’s only because of this technology and this advanced analysis that we were able to find them. Using older techniques, you would never know they were there.”
Dysregulated inflammation
It’s already well understood that PD-1 acts like a brake on the immune system, preventing T-cells from attacking the body’s normal tissue. In cancer therapy, a class of immunotherapy drugs called checkpoint inhibitors specifically blocks PD-1 expression on T-cells.
The idea in cancer is to “take the brakes off” and give T-cells free rein to fight a tumor. But in pediatric acute liver failure, Dr. Emamaullee says, the opposite effect may be needed. Instead of releasing the PD-1 brake, you may need to apply it.
“In acute liver failure, you have this dysregulated inflammation occurring,” she explains. “It appears that you may need T-cells expressing PD-1 to shut down this inflammation and let the liver recover. This also opens up a potential therapeutic target. If we could give a treatment that increases PD-1 expression, then maybe we could shut down this acute inflammation.”
She adds that PD-1 may also play a key role in liver transplant rejection—another area her team is studying. “We think that these cells are likely important for mediating liver inflammation overall,” she notes. “That could have implications for many different kinds of inflammatory liver disorders.”
The team’s next step is to study a larger sample of patients, with the goal of better understanding the role these particular T-cells play, as well as their spatial interactions with other cell types in the areas of inflammation. The researchers are also investigating the degree of liver regeneration that occurs during recovery from pediatric acute liver failure.
Study co-authors were Johanna Ascher Bartlett, MD, of CHLA; Tricia Saputera of USC; Sarah Bangerth, Arianna Barbetta and Bryce Roper, of the Keck School of Medicine of USC; and Carly Weaver and Rohit Kohli, MBBS, MS, of CHLA. Pediatric Pathologist Shengmei Zhou, MD, also of CHLA, is a research collaborator with the team.
Learn more about liver care at Children’s Hospital Los Angeles.
