Development of humanized mouse models to study severe asthma pathogenesis and evaluate novel mechanisms of benralizumab therapy 4514

Abstract Description Asthma is one of the common immunological disease characterized by airway hyperresponsiveness (AHR), excessive mucus production, and airway eosinophilia. Conventional mouse models have provided insights into type 2 cytokine roles in asthma but are limited by differences between rodent and human immune systems. To overcome this, we developed humanized mouse models to study severe asthma mechanisms and evaluate therapies. Using NOG hIL-3/hGM-CSF/hIL-5 triple transgenic mice engrafted with human hematopoietic stem cells, we established asthma models mimicking key features, including AHR, goblet cell hyperplasia, and eosinophilic airway inflammation, induced by human IL-33. Anti-human IL-13 antibody treatment significantly reduced these asthmatic pathologies by suppressing IL-13 produced from mast cells and basophils. Benralizumab, an anti-human IL-5R antibody, also attenuated AHR, eosinophilic inflammation, and mucus hyperproduction. Single-cell RNA sequencing revealed the novel effects of benralizumab that reducing IGHE+ B cells and downregulating IL-13 produced from the oxidative phosphorylation-associated mast cell cluster. These findings suggest that benralizumab exerts novel effects beyond eosinophil depletion, including modulation of B cells and mast cells. Our humanized mouse models provide a valuable platform for the preclinical evaluation of therapeutic strategies, advancing our understanding of severe asthma. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)