Engineered immune cells suppress asthma symptoms in allergic mice

Genetically engineered CAR T cells expressing artificial receptor proteins are increasingly used in the clinic to boost the immune system's response against leukemias and other cancers. In a study to be published July 6 in the Journal of Experimental Medicine (JEM), researchers in Switzerland have adapted this approach to suppress the immune system's response to a common allergen, reducing or preventing asthma symptoms in mice. The technique could eventually be used to treat a wide variety of allergies in humans.

Asthma affects over 300 million people worldwide, around 60% of whom suffer from allergic asthma. Allergens such pollen trigger an immune response in a patient's airways, causing inflammation, excessive mucus production, and difficulty in breathing. Allergen immunotherapy, which involves the administration of gradually increasing doses of allergen, is the only treatment that addresses the underlying cause of asthma. Yet, it is not recommended for patients with severe asthma, representing the most vulnerable population at greatest risk of asthma-related morbidities and mortality.

"This highlights the need for new, safe, and durable treatments for restoring allergen tolerance in severe allergic asthma," says Yannick D. Muller, an associate professor at Lausanne University Hospital and the University of Lausanne who led the new JEM study.

Regulatory T cells (Tregs) are immune cells that can dampen the body's immune responses and prevent excessive inflammation. Tregs are being investigated as potential therapies for a variety of inflammatory and autoimmune disorders, but their effectiveness is limited by their lack of specificity.

Muller and colleagues wondered whether they could boost the therapeutic potential of Tregs by genetically engineering them to express receptor proteins that recognize specific allergens. This approach is analogous to the CAR T cell method that is now commonly used to treat cancers: cytotoxic T cells are engineered to express chimeric antigen receptors that specifically recognize proteins on the surface of cancer cells, directing the immune system to attack and kill the tumor cells.

Muller's team constructed chimeric allergen receptors (CAlleRs) that specifically recognize a component of birch tree pollen, a leading cause of allergic asthma to which 8–16% of the European population are sensitive. These CAlleRs were based on antibodies isolated from a birch-allergic patient, linked to protein signaling domains that can activate Treg cells. Exposure to the birch pollen allergen, when stabilized by noncompetitive antibodies, boosted the suppressive activity of Tregs expressing these CAlleRs. Thus, the researchers found that simultaneous binding by a CAlleR and a non-competing antibody promotes receptor–allergen cross-linking underlying a novel mechanism to induce T cells activation by soluble antigens.

Muller and colleagues injected these CAlleR-expressing Tregs into mice that were already allergic to birch pollen. When these animals were re-exposed to birch pollen, they showed decreased signs of allergic inflammation, reduced mucus production, and increased lung function.

Next, the researchers injected CAlleR-expressing Tregs into mice that had never been exposed to birch pollen. When these animals were subsequently exposed to pollen, they failed to develop any asthma symptoms.

Our study provides proof-of-concept and preclinical evidence that CAlleR Tregs redirected against a birch pollen allergen can downmodulate birch pollen–nduced allergic asthma. Future studies should evaluate the persistence and stability of CAlleR Tregs over time and define the optimal modalities for implementing such a therapeutic approach."

Yannick D. Muller, associate professor at Lausanne University Hospital and University of Lausanne

CAlleRs could also be developed that specifically suppress the immune response to other common allergens, including house dust mites or certain food allergens.