AAAAI-funded research to probe new discoveries in EoE, interferon signaling

Key takeaways:

• Research will follow up on the recent discovery of interferon response gene signatures in patients with EoE.
• Findings could be quickly translated into new treatments with already-approved drugs.

Researchers will study connections between eosinophilic esophagitis and interferon signaling, possibly paving the way for new treatments, with funding from the AAAAI Foundation’s 2023 Faculty Development awards.

Funding for the investigation comes after researchers discovered interferon response gene signatures in the esophageal tissue of patients with EoE in the laboratory of David A. Hill, MD, PhD, FAAP, FAAAAI, at Children’s Hospital of Philadelphia.

“This pathway was not previously thought to be involved in EoE, and, as such, there is large potential for new discoveries,” Hill told Healio. “If we find that interferons are relevant to EoE, there are several drugs that are already approved for other diseases that alter interferon signaling.”

Hill said it would be “highly feasible” to translate new insights into the testing of a new therapeutic for EoE, which affects an increasing portion of the U.S. population and “many children” who see him for care.

The Hill Lab previously modeled EoE and found esophageal epithelial cells (EECs) expressing MHC class II molecules, which interferons induce to regulate mucosal homeostasis. Now, researchers will learn more about how that mechanism works during EoE-like inflammation using “state-of-the-art” mechanistic studies of several new mouse models and translational studies using human samples, Hill said.

In ovalbumin-based mouse models of food-driven EoE, researchers will use an EEC-specific Cre recombinase to conditionally delete interferon receptors of either type 1 or type 2, isolating their contributions and shedding light on the mechanisms that regulate EEC MHC II expression. They will also conditionally delete gene exons in EECs to study the influence of MHC II expression on esophageal T-cell functions and EoE-like reactions.

Outcomes are set to include antigen presentation, T-cell activation, esophageal inflammation and overall health. The study marks “the first step toward therapeutically modulating interferon signaling to complement existing therapies and improve EoE outcomes,” Hill said.

Hill credited his “longstanding mentor and adviser,” Jonathan Spergel, MD, PhD, chief of Children’s Hospital of Philadelphia’s allergy program, as “the reason” that he became interested in EoE, as well as a “wish to bring a new medication into the clinic” for his own patients.

Reference:

• Ballas ZK. J Allergy Clin Immunol. 2023;doi:10.1016/j.jaci.2023.03.002.

For more information:

David A. Hill, MD, PhD, FAAP, FAAAAI, can be reached at HillD3@chop.edu. Learn more about the Hill Lab at www.med.upenn.edu/hilllab/.