Findings May Lead to New Strategies for GVHD

A recent study in mice demonstrates that activating signaling pathways associated with antiviral immunity can help protect the intestinal epithelium from damage caused by chemotherapy and radiation. The findings may help in developing strategies to prevent graft-versus-host disease (GVHD) following stem cell transplantation to treat leukemia and other blood disorders.

In the study, published in Science Translational Medicine, researchers injected mice with agonists that activate the RIG-I and STING signaling pathways, which are normally associated with triggering immune responses. Compared with a control group, mice that received the treatment at least one day before undergoing chemotherapy and radiation experienced less damage to the small intestine and were less likely to develop GVHD.

“We found that pathways that are usually used to fight tumors can also induce regenerative processes,” says the study's senior investigator Hendrik Poeck, MD, a researcher at the Technical University of Munich in Germany. “The RIG-I and STING pathways are usually used to fight cancer because they incite proinflammatory processes. However, we found that under certain conditions, they can also be protective.”

Patients who undergo stem cell transplantation are vulnerable to GVHD following chemotherapy and radiation, which cause damage to the intestinal epithelial cells that normally protect the gut. The intestine subsequently becomes susceptible to invasive bacteria, which triggers activation of aggressive donor T cells.

Poeck's team theorized that protecting the epithelium before transplantation might lower the risk of an immune attack. They chose to work with the RIG-I and STING proteins because both are part of signaling chains that cause production of IFN1, which has been shown to accelerate regeneration of epithelial cells in addition to triggering immune responses.

The timing of treatment was crucial, Poeck says. “The main function of IFN1 is proinflammatory, so if you stimulate these pathways in a patient who has already been harmed by chemotherapy or undergone transplantation, it probably doubles the proinflammatory effect and could be harmful.”

The findings point to the possibility of developing more targeted treatments to combat GVHD, notes Pavan Reddy, MD, a hematologist-oncologist at the University of Michigan in Ann Arbor, who was not involved with the study. Novel strategies that mimic IFN1 or promote RIG-I/STING pathways locally in the gastrointestinal tract have the potential to reduce systemic damage while leveraging the beneficial effects on GI cells.

Correct dosing and scheduling will be key in developing treatments that mimic the action of IFN1, which has myriad effects on the immune system, he notes. However, this study opens up new opportunities for research.

“The finding that the RIG-I and STING pathways have protective effects is a novel observation as these pathways have been largely studied only in immune cells,” he says. “This study adds to an exciting and growing body of evidence that strategies that target tissues directly might be useful adjuncts in our armamentarium for effectively grappling with this complex and difficult disease.” –Janet Colwell