Researchers identify a new player in graft-versus-host disease and organ transplant rejection

March 19, 2021

A long noncoding RNA whose function was previously unknown turns out to play a vital role in mobilizing the immune response following a bone marrow transplant or solid organ transplantation, according to a new study from the University of Michigan Rogel Cancer Center and Michigan Medicine as reported in a news release.

This RNA molecule, cataloged in scientific databases simply as Linc00402, helps activate immune defenders known as T cells in response to the presence of foreign human cells.

The investigation, which included samples from more than 50 patients who underwent a bone marrow or heart transplant, suggests inhibiting the RNA therapeutically might improve outcomes for transplant recipients. Their findings appear in Science Translational Medicine.

“We see a lot of graft-versus-host disease — or GVHD — which is a potentially fatal complication that can happen after transplant when T cells in the donor’s blood see the transplant recipient’s cells as invaders and attack them,” said study lead author Daniel Peltier, MD, PhD, Pediatric Bone Marrow Transplant Physician at U-M. “Unfortunately, the medicines we use to prevent GVHD suppress the immune system and can raise the risk of a cancer relapse or infection, and they also have other side effects.”

In taking a deep dive into the biology, researchers hoped to find a way of targeting just the problematic components of the immune system that cause GVHD.

One reason for looking at this particular type of RNA molecule is that they tend to be expressed only by a limited number of tissues in a limited number of contexts, explains senior study author Pavan Reddy, MD, Deputy Director of the Rogel Cancer Center and Division Chief of Hematology/Oncology at Michigan Medicine.

“So, unlike a lot of RNAs, which are expressed in all kinds of cells by all kinds of living things, long noncoding RNAs offer the possibility that we might be able to target them in a relatively unique and disease-specific way,” he said.

The research project began with a database of blood samples from a range of patients who had undergone a bone marrow transplant at Michigan Medicine. Some patients had closely matched donors, while others had what doctors call mismatched donors.

Then, using RNA sequencing, the research team looked for patterns across the bone marrow transplant patients. Their findings were validated in two other cohorts of patients using different methodologies.

Since Linc00402 gets improperly activated in the presence of foreign cells, the researchers also conducted experiments to see if they saw the same response in the presence of another type of invader: a viral infection. But they didn’t see elevated levels of the RNA in response to the virus.

“This strongly suggests that this dysregulation is a change you only see when you put a T cell from one human being into another,” Reddy says.

Through a series of experiments, the researchers dug deeper into the RNA and its behavior. They used genetic tools like CRISPR and gapmers to silence the gene that makes it and lentiviruses to amplify it. And this revealed that Linc00402 plays a key role in T cells’ ability to respond to a threat by proliferating.

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