Engineered CAR-like Tregs Suppress Allergic Asthma in Mice, Offering Blueprint for Novel Allergy Immunotherapy
核心洞察
Swiss researchers engineered regulatory T cells with chimeric allergen receptors (CAlleRs) that specifically recognize birch pollen, reducing or preventing asthma symptoms in allergic mice.
The CAlleR Treg approach adapts CAR T cell technology from oncology to suppress, rather than activate, immune responses against common allergens.
In preclinical models, CAlleR Tregs decreased allergic inflammation, reduced mucus production, and improved lung function upon allergen re-exposure.
Swiss researchers have successfully adapted chimeric antigen receptor (CAR) T cell technology—widely used in oncology—to suppress allergic immune responses, demonstrating that genetically engineered regulatory T cells can reduce or prevent asthma symptoms in mouse models. The findings, published July 6 in the Journal of Experimental Medicine (JEM), open a potential new therapeutic avenue for severe allergic asthma (搜索) and other allergies where current treatments fall short.
Asthma affects over 300 million people worldwide, and approximately 60% of those cases are classified as allergic asthma (搜索). Allergen immunotherapy, which involves administering gradually increasing doses of allergen, remains the only treatment that addresses the underlying cause of the disease. However, it is not recommended for patients with severe asthma, "representing the most vulnerable population at greatest risk of asthma-related morbidities and mortality," said Yannick D. Muller, associate professor at Lausanne University Hospital and the University of Lausanne, who led the study.
"This highlights the need for new, safe, and durable treatments for restoring allergen tolerance in severe allergic asthma (搜索)," Muller added.
From cancer-killing CARs to allergy-suppressing CAlleRs
Regulatory T cells (Tregs) are immune cells capable of dampening immune responses and preventing excessive inflammation. While Tregs are under investigation as potential therapies for inflammatory and autoimmune disorders, their clinical utility has been limited by a lack of specificity.
Muller and colleagues hypothesized that the therapeutic potential of Tregs could be enhanced by genetically engineering them to express receptor proteins that recognize specific allergens—an approach analogous to CAR T cell therapy, in which cytotoxic T cells are engineered with chimeric antigen receptors that target cancer cells.
The team constructed chimeric allergen receptors (CAlleRs) designed to specifically recognize a component of birch tree pollen, a leading cause of allergic asthma (搜索) to which 8–16% of the European population are sensitive. These CAlleRs were built using antibodies isolated from a birch-allergic patient and linked to protein signaling domains capable of activating Treg cells.
A key mechanistic insight emerged: exposure to the birch pollen allergen (搜索), when stabilized by noncompetitive antibodies, boosted the suppressive activity of CAlleR-expressing Tregs. The researchers found that simultaneous binding by a CAlleR and a non-competing antibody promotes receptor–allergen cross-linking, representing a novel mechanism for inducing T cell activation by soluble antigens.
Preclinical efficacy in both treatment and prevention models
In the first set of experiments, Muller and colleagues injected CAlleR-expressing Tregs into mice already allergic to birch pollen. Upon re-exposure to the allergen, these animals showed decreased signs of allergic inflammation, reduced mucus production, and increased lung function compared to controls.
In a second, more stringent test, the researchers administered CAlleR Tregs to mice that had never been exposed to birch pollen. When these animals were subsequently exposed to the allergen, they failed to develop any asthma symptoms—suggesting that the engineered cells may have both therapeutic and prophylactic potential.
"Our study provides proof-of-concept and preclinical evidence that CAlleR Tregs redirected against a birch pollen allergen (搜索) can downmodulate birch pollen–induced allergic asthma (搜索)," Muller stated. "Future studies should evaluate the persistence and stability of CAlleR Tregs over time and define the optimal modalities for implementing such a therapeutic approach."
Broader implications for allergic disease
The researchers noted that CAlleRs could be developed to specifically suppress immune responses to other common allergens, including house dust mites and certain food allergens, potentially broadening the platform's applicability beyond respiratory allergy. The approach represents a conceptual shift: rather than broadly suppressing the immune system, CAlleR Tregs offer a targeted strategy to restore allergen-specific tolerance—a long-sought goal in allergy treatment.