Severe allergic reactions can be swift and deadly. Two new studies of mice, published August 7 in Science, reveal a key step in this terrifying cascade. What’s more, these findings hint at a drug to prevent it.
Anaphylaxis is a life-threatening allergic reaction commonly triggered by insect stings, medications and foods such as peanuts or eggs. After exposure to the allergen, a person’s immune system can overreact, leading to swelling, trouble breathing and dangerously low blood pressure.
Once underway, these extreme reactions can be stopped with epinephrine, administered either as an injection or, as of 2024, a nasal spray. This hormone helps open airways and shrink blood vessels, among other actions. But it doesn’t always work.
“Epinephrine only treats anaphylaxis once it has already occurred,” says immunologist Tamara Haque of Indiana University School of Medicine in Indianapolis. “We need treatments to prevent this severe reaction before it starts.”
By studying mice that develop signs of anaphylaxis after repeated exposure to food allergens, the new studies identified a key signal in the gut that kicks off anaphylaxis — molecules known as leukotrienes.
In the gut, bits of food get ferried across an intestinal membrane to reach the bloodstream, where they can trigger anaphylaxis. This outsized reaction comes courtesy of mast cells, protective immune cells that sense dangers, real or perceived, and prompt the body to respond. Leukotrienes, one study found, help regulate this ferry ride across the gut membrane.
“Once we realized what pathway we were studying, it was also immediately obvious how we might be able to block it,” says Stephanie Eisenbarth, an immunologist at Northwestern University Feinberg School of Medicine in Chicago and coauthor of one of the papers. No transport, no anaphylaxis, the reasoning went. “Unless there’s a ferry that gets [the food allergen] across, the mast cells on the other side will never know that it was there, and they will not respond,” Eisenbarth says. “They won’t induce this anaphylactic response.”
Sure enough, a drug already approved for asthma, called zileuton, did just that. Mice’s reactions to a food allergen (peanut in one study, egg in the other) were diminished on zileuton.
These findings relate only to allergic reactions caused by food that gets to the gut; stings and other allergens probably work differently. Injected allergens, for instance, didn’t seem to rely on leukotrienes to alert the immune system, says Nathaniel Bachtel, an immunologist at Yale University and coauthor of the other paper. That work also uncovered details about the specialized populations of mast cells that proliferate in the gut lining.
The details of how allergens can trigger reactions are incredibly complex and still poorly understood, Bachtel says. But both studies point to leukotrienes as key steps in food allergen reactions, making the molecules worth more scrutiny. “It’s kind of a strange thing, and in retrospect, it’s a little bit surprising to me that this pathway hadn’t been looked at this carefully,” he says.
For now, Haque says, it’s not clear how this process works in people, but there are good reasons to suspect that mice and people are similar. “These data strongly suggest that it is worth conducting human studies.”
Eisenbarth, along with study coauthor Adam Williams and others, has a clinical trial in the works. The first step will be to test whether zileuton affects how well peanut particles cross the intestinal barrier in people with allergies to different foods, says Williams, an immunologist also at Northwestern. In these preliminary tests, scientists will study people with allergies, but not to peanuts, for safety reasons.
The necessary experiments will take time to complete, but Williams is optimistic. “We are making progress faster now than at any point in the history of allergy research,” he says. “And so, there’s hope.”
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