Our bodies come equipped with a mechanism that naturally holds food allergies in check. A research team from Juntendo University and Hiroshima University has shown in mice that a molecule called "soluble ST2," kept at high concentrations in the body, is what does the work. For a condition whose management still comes down to avoiding the trigger food, that opens the possibility of targeting the suppression mechanism itself.

Background: Why Do Food Allergies Occur?

Food allergy is a condition in which the immune system overreacts to foods that should be harmless. In recent years the number of patients has risen in developed countries, including Japan, and most cases begin in early childhood.

At its core is an immune response called "type 2 inflammation." When food antigens enter the body, epithelial cells are damaged and release a cytokine called IL-33 (interleukin-33), which activates immune cells and triggers the symptoms.

IL-33's receptor, "ST2," comes in two forms: membrane-bound ST2 (ST2L) on cell surfaces, and soluble ST2 (sST2) in the blood and other fluids. When membrane-bound ST2 captures IL-33, it transmits a signal that promotes allergy. Soluble ST2, by contrast, was thought to act as a "decoy," capturing IL-33 and blocking that signal. But its actual role in the body had long been a mystery.

Solving the Mystery with Genetically Modified Mice

A collaborative team took on the question: Associate Professor Kumi Izawa, Professor Jiro Kitaura and Center Director Ko Okumura of the Atopy Research Center at Juntendo University Graduate School of Medicine; Mayuki Kojima of the Department of Pediatrics; Professor Hiromichi Tokai and Specially Appointed Professor Toshiaki Shimizu of pediatric and adolescent medicine; and Professor Susumu Nakae of Hiroshima University.

They succeeded in creating genetically modified mice that express membrane-bound ST2 normally but lack only soluble ST2. Separating the two receptor forms made it possible to test the role of soluble ST2 directly.

Fibroblasts Hold the Key

The first finding concerned the source. "Fibroblasts" in the skin and small intestine turned out to produce far more soluble ST2 than mast cells, and to do so constantly. Cells known mainly for holding tissue together were also working on allergy suppression.

When food allergy was induced in mice lacking soluble ST2, symptoms were markedly worse than in normal mice. The number of mast cells in the small intestine, their degranulation rate (how often they release the substances that cause allergic symptoms), and levels of inflammatory cytokines such as IL-33 all rose.

The reverse test held as well. Giving the deficient mice "ST2-Fc," a substance that mimics soluble ST2, brought mast cell numbers and degranulation rates back down and eased the symptoms.

Hope for New Treatments

The findings were published in the Proceedings of the National Academy of Sciences (PNAS) on January 5, 2026.

One direction the team points to is a drug that selectively raises only the body's own soluble ST2. Biologics that block IL-33 signaling are also in view.

The latter has already reached the clinic. In the United States, a phase 2a trial of the anti-IL-33 antibody etokimab enrolled 20 adults with peanut allergy; 15 days after a single dose, 73% could tolerate 275mg of peanut protein, against 0% on placebo. The difference at day 45 was not statistically significant, however, and the trial was small and preliminary. The present study thickens the scientific case behind that line of work.

IL-33 signaling reaches well beyond food allergy, into infections, tumors, cardiovascular disease and metabolic disorders. The mice created here double as a tool for working out what soluble ST2 does in each of those settings.

The Current State and Challenges of Food Allergies

In Japan, food allergy prevalence runs about 10% in infants, 5% in three-year-olds, and 1.3-4.5% from school age onward, with roughly 1-2% across all ages. Eggs, milk and wheat were long the three leading causes, but tree nuts, walnuts and cashews in particular, have climbed sharply in recent years.

Current treatment rests mainly on avoiding the trigger food; no fundamental cure exists. Oral immunotherapy (gradually consuming small amounts of the trigger food to build tolerance) is being studied, but it does not work for every patient and carries risks of serious reactions such as anaphylaxis.

The role of soluble ST2 uncovered here approaches the problem from a different angle: rather than suppressing the immune system from outside, raise the brake the body already has. The results so far are in mice, and the distance to human application remains considerable.

Food allergies are increasing worldwide, but trigger foods, access to treatment, and social responses differ greatly from country to country. In Japan, allergy-aware school lunches are spreading and food-labeling rules are in place, yet many challenges remain.

What is being done about food allergies in your country? Where do research and treatment stand? Please share your thoughts in the comments.

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