Targeting IL-18 may improve treatment for eosinophilic esophagitis

Key takeaways:

• Allergens trigger the release of IL-18, which produces eosinophils that build up in the esophagus.
• Current treatment targets IL-4-alpha, which may have long-term impacts on brain function.

Inhibiting the NLRP3 pathway and the release of IL-18 may prevent the development of eosinophilic esophagitis, according to a study published in Nature’s Communications Biology.

These findings challenge decades of thinking that Th2 cells play a major role in triggering the disease, Anil Mishra, PhD, MS, director, Tulane Eosinophilic Disorders Center, section of pulmonary diseases, Tulane University School of Medicine, and colleagues wrote.

“Eosinophils are not produced by IL-4,” Mishra told Healio, adding that IL-13 is not involved in eosinophilic production either. “They support the disease process, but they are not the initiator of the disease.”

Also, Mishra said, IL-5 produces naïve eosinophils, but not pathogenic eosinophils.

However, Mishra and his colleagues found that allergens activate the NLRP3 inflammasome pathway, which regulates the innate immune system. When allergens enter the body, they trigger the release of IL-18 and other proinflammatory proteins, the researchers said.

These proteins then produce eosinophils, which accumulate in the lining of the esophagus to cause eosinophilic esophagitis. The esophagus then shortens and its wall thickens, making it difficult to swallow and causing food to get stuck in the throat.

The researchers used immunofluorescence analysis to examine the expression of NLRP3, the caspase-1 inflammatory caspase, and IL-18 in biopsies from patients with active EoE and from healthy patients.

“That caspase is inducing IL-18,” Mishra said.

The healthy patients had very few anti-cytokeratin⁺ NLRP3⁺ cells, anti-NLRP3⁺CD163⁺ macrophages, anti-NLRP3⁺caspase-1⁺ cells and anti-NLRP3⁺IL-18⁺ compared with the induced expression of these factors in the patients with active EoE.

Also, the patients with active EoE had significantly higher levels of anti-CD163⁺, anti-NLRP3⁺, anti-caspase-1⁺ and anti-IL-18⁺ cells compared with the healthy patients, the researchers said.

The biopsies from the patients with active EoE additionally had high counts of esophageal intact eosinophils and extracellular eosinophilic granules, whereas the biopsies from the healthy patients had no detectable eosinophils.

The patients with active EoE had approximately a hundred times the number of anti-EPX eosinophils compared with the healthy patients as well, in addition to high levels of IL-18 that correlated with tissue eosinophilia.

Also compared with the healthy patients, the patients with active EoE had increased transcript levels of CD163, NLRP3 and caspase-1 from tissue RNA based on real-time polymerase chain reaction analysis.

Based on these findings and on the results from murine models also included in the study, the researchers called epithelial cell- and macrophage-induced NLRP3-regulated IL-18 mechanistically critical in promoting EoE induced by aeroallergens and food allergens.

Findings also illustrated how the overexpression of IL-18 promotes the pathogenesis of EoE, including the proliferation of intraepithelial eosinophil and epithelial cells in murine models.

These results support previous research showing how IL-18 differentiates and transforms naïve eosinophils generated by IL-5 into pathogenic eosinophils, the researchers said, in addition to showing how IL-18 deficiency and neutralization have protective effects against allergen-induced EoE.

“When we have the neutralization of IL-18, we saw that those eosinophils are pretty much gone,” Mishra said, adding that the researchers observed the same disease revision when NRLP3 and caspase were blocked.

By targeting neutralized IL-18, the researchers said, NLRP3 and caspase-1 inhibitors may be a novel therapeutic strategy for EoE.

“IL-18 may be a normal marker, a normal way to treat eosinophilic esophagitis,” Mishra said. “That’s the way we are proceeding now.”

As an IL-4R-alpha antibody, dupilumab (Dupixent, Sanofi/Regeneron) improves some EoE symptoms, the researchers said. Mishra noted that other treatments that target IL-4 and IL-5 reduce eosinophil counts too, but he did not consider them promising.

“The eosinophil numbers are down. That is true. The eosinophil number will be down because IL-5 is a growth and survival factor. But IL-5 is not targeting the real eosinophils,” he said, adding that other effects are emerging with these treatments.

IL-4 is critical to memory, learning and other higher functions in the brain, the researchers cautioned. Treatment that inhibits cytokines including IL-4 and IL-5 also may compromise the developing innate immunity of pediatric patients with EoE as well, the researchers added, indicating a need to examine the long-term effects of its use.

“All the inflammatory cells are targeted by the IL-18. The IL-5 and IL-4 are only targeting eosinophils. And of course, EoE is not an eosinophilic-specific disease. This is a complex disease,” Mishra said. “Not only eosinophils, but basophils, mast cells, they are all involved.”

But pretreatment with NLRP3 and caspase-1 inhibitors such as MCC950, BHB and VX-765 was protective against food-induced and aeroallergen-induced EoE pathogenesis without these risks in an experimental model, the researchers said.

Noting this therapy’s potential to improve outcomes for patients with EoE, the researchers recommended multicentral, double-blind human clinical trials using VX-765, which they called a potent and selective inhibitor of the IL-18 converting enzyme/caspase-1 subfamily.

“Existing trials are targeting only eosinophils, not targeting other cells,” Mishra said.

Mishra is now seeking funding to develop IL-18 for human use and said that he has been in talks with government agencies and private corporations. He expects funding to come in sometime in the next 3 or 4 months, with development taking another year and a half after that.

Reference:

• This disease can be caused by a food allergy and prevent children from eating. A new study may show how to treat it. https://medicine.tulane.edu/news/disease-can-be-caused-food-allergy-and-prevent-children-eating-new-study-may-show-how-treat-it. Published July 31, 2023. Accessed Aug. 11, 2023.

For more information:

Anil Mishra, PhD, MS, can be reached at amishra@tulane.edu.