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For millions of people around the world, asthma is more than just a breathing problem — it is a chronic and often debilitating condition caused by the immune system's exaggerated response to harmless airborne particles.

Traditional treatments like inhaled steroids and bronchodilators help manage symptoms but fail to address the underlying cause: the immune system's misdirected attack on respiratory allergens.

But what if we could reprogram the immune system to tolerate these allergens rather than react with inflammation?

A team of researchers led by , Vice President of Life Sciences and Engineering at New York University and Professor of Chemical and Biomolecular Engineering at NYU Tandon, of Biology and Chemistry at NYU Faculty of Arts and Science, and Biochemistry and Molecular Pharmacology at NYU Langone Health along with researchers at the UChicago Pritzker School of Molecular Engineering have developed a new therapy that does just that — by enlisting an unexpected ally: the liver.

A New Approach to an Old Problem

At the heart of asthma is a dysfunctional immune response. In allergic individuals, exposure to common allergens such as dust mites, pollen, or pet dander triggers an overproduction of inflammatory signals, leading to airway constriction and excessive mucus production.

Current immunotherapy treatments attempt to retrain the immune system by repeatedly exposing it to small doses of the allergen over months or even years. However, this approach is slow, has variable success, and carries the risk of triggering severe allergic reactions.

In their , Hubbell and his colleagues at the UChicago Pritzker School of Molecular Engineering, including lead author Jorge Emiliano Gómez Medellín, introduced a novel form of allergen immunotherapy called liver-targeted immunotherapy (LIT). Unlike traditional allergy shots or sublingual tablets, LIT exploits the liver’s natural ability to promote immune tolerance.

“The liver has long been known as a unique organ, capable of suppressing immune responses to harmless antigens from food and blood-borne particles,” says Jeffrey Hubbell, a senior author of the study. “We wondered—could we harness this natural tolerance mechanism to turn off allergic reactions?”

Engineering a Smarter Allergy Shot

To achieve this, the researchers chemically modified allergens by synthetically attaching sugar molecules called mannose to their surfaces. This process, known as synthetic mannosylation, allows the allergens to bypass the immune system’s usual alarms and instead be delivered directly to the liver. There, specialized immune cells reprogram the response from one of inflammation to tolerance.

In preclinical trials, mice that received LIT developed a robust population of regulatory T cells—immune cells that act as peacekeepers, instructing the body to ignore allergens rather than attack them. Remarkably, just two doses of the therapy provided year-long protection against allergic asthma symptoms.

“The speed and durability of this treatment are unprecedented,” says Hubbell. “Traditional allergen immunotherapy can take years to work. With LIT, we’re seeing long-lasting immune tolerance after only two interventions.”

One of the biggest risks of current allergy treatments is the potential for severe allergic reactions, including life-threatening anaphylaxis. This happens when the immune system mistakes the introduced allergen as a threat and mounts an aggressive defense.

To test whether LIT could avoid this problem, the researchers administered their engineered allergens to sensitized mice—essentially a model for patients with severe allergies. Unlike unmodified allergens, which triggered dangerous immune responses, the mannosylated allergens did not provoke any allergic symptoms. Instead, they were quietly processed by the liver, leading to a significant reduction in airway inflammation.

“Given this improved safety profile and the effective long-term tolerance without continuous treatment, it is tempting to weigh the benefits of LIT with its novel administration,” says Trevor W.M. Ung, co-lead in the project from UChicago PME.

A Future Beyond Asthma?

While this study focused on allergic asthma, the principles of LIT could be extended to other allergic diseases, including food allergies and atopic dermatitis. “Given the fear caused by food-induced anaphylaxis, LIT has the potential to provide some relief to children and parents throughout by reducing this risk” Gómez Medellín says.

Additionally, since the approach relies on generating immune tolerance, it may hold promise for treating autoimmune diseases, where the immune system mistakenly attacks the body's own tissues.

The next step for the research team is to test LIT in human clinical trials after additional laboratory work targeting house dust mite allergy and food allergens. If the results hold up in people, this therapy could revolutionize the treatment of allergic diseases, offering a rapid, safe, and long-lasting solution to millions of patients worldwide.

For over a century, allergen immunotherapy has remained largely unchanged, relying on repeated exposure to allergens in hopes of gradually reducing sensitivity. LIT challenges this slow and risky process by leveraging the body's built-in tolerance mechanisms to achieve faster and safer results.

“Rather than fighting against the immune system’s natural tendencies, we’re working with them,” Hubbell explains. “This could be the future of allergy treatment—a way to not just manage symptoms, but to cure the disease at its source.”