Allergy & Immunology

Where current severe asthma biologics stop—and where cell therapies may take over

This review synthesizes mechanisms, efficacy, safety, and biomarker data for anti-IgE, anti–IL-5/IL-5R, anti–IL-4/13, and anti-TSLP biologics in severe asthma. It emphasizes endotype-based selection using patient-specific inflammatory profiles and biomarkers to individualize biologic choice and sequencing. The authors highlight key limitations, including long-term administration needs and limited impact on disease progression or structural remodeling. They outline cell-based approaches, such as Th2-to-Treg reprogramming, CAR-NK designs, and mesenchymal stem cell therapies, aiming for immune tolerance and functional cure. 1

Next-generation anti–β-tryptase antibody fully blocks tetrameric and monomeric activity

This mechanistic study describes an anti–β-tryptase antibody that inhibits both tetrameric and monomeric human β-tryptase, a major mast-cell mediator. The antibody binds an exosite, driving tetramer dissociation and allosterically altering the monomer’s substrate-binding cleft to abolish proteolysis. Cryo-EM and mutational analyses show that a single CDR-L3 Asp-to-Gly change preserves binding but eliminates inhibitory function, defining the allosteric pathway. Structure-based engineering increased inhibitory potency several-fold by optimizing charge–charge interactions at the binding interface, supporting development of highly potent tryptase inhibitors for allergic disease. 2

PM2.5 worsens HDM-driven allergic rhinitis via STING-dependent barrier disruption

Mouse and human nasal epithelial models showed that PM2.5 plus house dust mite synergistically aggravated allergic rhinitis versus either exposure alone. Co-exposure increased Th2 inflammation, with higher IL-4, IL-5, IL-13, IgE, and more severe nasal symptoms in vivo. Nasal epithelial barrier markers E-cadherin and Claudin-1 were downregulated, while STING/NF-κB signaling was activated in tissue and cultured cells. A STING inhibitor, H-151, reversed epithelial barrier damage, Th2 skewing, and rhinitis-like features, identifying STING as a therapeutic target in pollution-aggravated aeroallergy. 3

Esophageal PSMB8 expression predicts PPI nonresponse in pediatric EoE

In 48 pediatric eosinophilic esophagitis patients, pre-treatment esophageal biopsies revealed distinct immunologic transcriptomes between PPI responders and nonresponders. Thirteen differentially expressed genes were identified, largely related to antigen processing and presentation pathways. PSMB8 emerged as a hub gene with significantly higher expression in PPI-nonresponders, confirmed by immunohistochemistry in an expanded 62-patient cohort. ROC analysis showed PSMB8 highly predictive for PPI response, with reported specificity of 1.00, suggesting utility for selecting initial therapy. 4