People with severe allergies who don’t respond to antihistamines may consider allergen immunotherapy. Whether in the form of weekly injections at an allergy clinic or daily doses of liquid dissolved beneath the tongue, the goal of this treatment strategy is to expose a person to higher and higher doses of an allergen, gradually training their immune system to tolerate the substance.

The existing forms of allergen immunotherapy ultimately pay off for many people with allergic rhinitis — seasonal allergies, for example — and asthma, but achieving relief requires years of regular doses, any one of which could cause uncomfortable or even dangerous allergic reactions (1). That’s why Emiliano Gómez Medellín, a molecular engineering postdoctoral researcher at the University of Chicago, and his colleagues set out to design a faster-acting and safer allergen immunotherapy.

Once these T cells are induced, and they’re maintained in the body, they have the potential to give durable control of the disease. 
- Emiliano Gómez Medellín, University of Chicago

Working with University of Chicago immunologist Jeffrey Hubbell and his group, Gómez Medellín and his colleagues developed a liver-targeted immunotherapy for egg and house dust mite allergens, which provided lasting relief for mice without eliciting an allergic response. The researchers described their results in a recent Science Translational Medicine study (2).

The liver is responsible for processing toxic substances from the gut and dead cells from the blood, and while doing so, it communicates with the immune system to promote tolerance of certain antigens from food and the body. This process results in both a reduction in inflammatory T cells and an increase in regulatory T cells, which keep their inflammatory counterparts in check. 

Previously, Hubbell’s group showed that they could direct antigens that play a role in type 1 diabetes to a mouse’s liver cells by tagging the molecules with sugar (3). The liver cells then presented the antigens, altering the way T cells responded to the substances and making the mice less prone to developing diabetes.

To explore whether this same strategy might work for allergen immunotherapy, Gómez Medellín and his colleagues attached the sugar mannose to the chicken egg protein ovalbumin, which researchers commonly use to model allergic asthma in mice. The researchers checked to see if the resulting molecule, called a tolerogen, could protect mice from ever developing allergies. They found that the mice that received the tolerogen maintained lower levels of allergic antibodies and had healthier lungs and airways than ones that didn’t. 

The effect of the tolerogen appeared to depend on the proliferation of ovalbumin-specific regulatory T cells. When Gómez Medellín’s team removed these immune cells, the tolerogen could not protect mice from developing allergic airway disease. The fact that the liver-targeted allergen immunotherapy induced the creation of regulatory T cells was particularly exciting for Gómez Medellín. “Once these T cells are induced, and they’re maintained in the body, they have the potential to give durable control of the disease,” he said. 

In fact, the researchers observed that the tolerogen conferred lasting protection when they gave it to mice that had already developed an ovalbumin allergy. A whole year after receiving an infusion of the tolerogen, the mice continued to have less severe reactions to the egg protein than their untreated counterparts. These early results offer promise that targeting immunotherapy to the liver could quickly induce lasting relief from allergies.

This experiment also provided evidence that liver-targeted immunotherapy is safe. The team discovered that adding the sugar to the egg protein prevented immune cells from recognizing it before it reached the liver, avoiding a dangerous allergic reaction. 

However, ovalbumin does not typically cause rhinitis or asthma in people, and it lacks a key feature that many allergenic proteins found in house dust mites, pollens, and other more common airway allergens have. These proteins, like the house dust mite’s Dermatophagoides pteronyssinus 1 (Der p 1), are enzymes that can cut apart other proteins, which appears to be key to their allergenic activity.

So, Gómez Medellín and his colleagues adapted their method to see if they could safely deliver Der p 1 to the liver of a mouse with a house dust mite allergy. Simply attaching a sugar molecule to Der p 1 and giving that tolerogen to mice caused severe allergic reactions, including life-threatening anaphylaxis. But if the researchers first modified Der p 1 slightly to render it incapable of cutting up other proteins and then attached the sugar molecule, the resulting tolerogen was safe. Furthermore, the mice that received infusions with this safe tolerogen had less severe reactions when they subsequently inhaled house dust mites.

Mark Kaplan, an immunologist at Indiana University, was particularly impressed by the success that the researchers ultimately had in preventing anaphylaxis by modifying the tolerogen. Whereas the goal of allergy shots and drops for rhinitis and asthma is often to reduce airway inflammation, Kaplan wondered if liver-targeted immunotherapy might prove more useful for people with an allergy that is likely to result in anaphylaxis. “This might be even more important if this were applied to a food allergy, for example,” he said.

Gómez Medellín also sees the potential to adapt this treatment strategy for food allergies. “That seems to be a rising problem in this country and worldwide,” he said. Like Kaplan, Gómez Medellín wants to use liver-targeted immunotherapy wherever it can have the greatest impact.

References

1. Fritzching, B. et al. Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: Results from the REACT study, a retrospective cohort study. Lancet Reg Health Eur  13, 100275 (2022).
2. Gómez Medellín, J.E. et al. Liver-targeted allergen immunotherapy rapidly and safely induces antigen-specific tolerance to treat allergic airway disease in mice. Sci Transl Med  17, eadl0406 (2025).
3. Wilson, D.S. et al. Synthetically glycosylated antigens induce antigen-specific tolerance and prevent the onset of diabetes. Nat Biomed Eng 3, 817-829 (2019).