Allergy最新文献

Background: IL-25 is a key epithelial-derived alarmin associated with T2-high asthma, yet its downstream mechanisms remain poorly defined. CD207 (Langerin)⁺ dendritic cells (DCs) are localized at the airway epithelial interface. However, whether these cells respond to epithelial-derived cytokines and contribute to the Th2 immune response in asthma remains unclear.

Methods: Single-cell RNA-seq from healthy human lungs was analyzed to define the transcriptomic features of CD207⁺ DCs. Their function was validated in a house dust mite (HDM)-induced asthma model using Cd207^-/- mice. Flow cytometry was performed on lung and mediastinal lymph nodes. DC-T cell co-cultures were used to assess Th2 polarization. Epithelial-DC interactions were evaluated using transwell co-culture with ALI-differentiated tracheal epithelial cells. Clinical relevance was examined in airway samples from asthma patients in the U-BIOPRED cohort.

Results: CD207⁺ DCs were enriched in intraepithelial compartments and exhibited increased MHC-II and Claudin-1 expression. In asthma, their abundance correlated with T2 signatures and Th2 markers (CRTH2, ST2). CD207 deletion reduced HDM uptake, Th2 cytokines, airway inflammation, and Th2 differentiation. IL-25 induced CD207⁺ DCs and enhanced their Th2-polarizing capacity in vitro. An IL-25-CD207 co-expression score correlated with IL-4/IL-5/IL-13 levels and was higher in steroid-naïve patients with severe asthma.

Conclusion: Our study identifies CD207⁺ DCs as epithelial-associated antigen-presenting cells that bridge IL-25 signaling and Th2 polarization in allergic asthma. Targeting the IL-25-CD207 axis may offer therapeutic opportunities for T2-high asthma.

Background: IgE-associated allergic diseases, affecting approximately 30% of the global population, are a major health burden. Standard treatments, including pharmacotherapy and allergen immunotherapy (AIT), have limitations such as adverse effects, insufficient symptom relief and long treatment durations.

Methods: In this study, we developed and evaluated a bispecific T-cell engager (TCE) and a half-life extended (HLE) bispecific natural killer (NK) cell engager (NKCE) targeting IgE-producing cells, to offer novel, potentially curative therapeutic options. The TCE and HLE-NKCE constructs were designed to target the CεmX domain of membrane-bound IgE (mIgE) and engage T cells and NK cells, respectively. Their efficacy was assessed through in vitro luciferase-based cytotoxicity assays using Ramos and U266 B-cell lines expressing mIgE as target cells, and primary human immune effector cells and the NK-cell line NK-92 as effector cells. Additional characterisation of the constructs was performed using flow cytometry.

Results: Both TCE and HLE-NKCE specifically mediated killing of CεmX-expressing cells in a dose- and effector-to-target (E:T) ratio-dependent manner. The TCE demonstrated robust activity even at low antigen densities and concentrations as low as 1 ng/mL (18 pM). The HLE-NKCE effectively mediated killing in the presence of human serum albumin, suggesting functionality in physiological conditions. T- and NK-cell activation was observed only in the presence of target cells and TCE.

Conclusion: Our novel anti-CεmX TCE and HLE-NKCE effectively target and eliminate mIgE-expressing cells in vitro. Although further investigation is needed, our bispecific engagers are promising off-the-shelf therapeutics for the treatment of IgE-associated allergic diseases.

Background: Dupilumab is an effective treatment for severe, uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). Most real-life studies have been conducted on small patient cohorts for up to 1 year.

Methods: This ambispective, multicentric, 2-year-long study evaluated dupilumab effectiveness (including treatment response, disease control, and remission) and safety in severe, uncontrolled CRSwNP patients from the DUPIREAL Italian study centers.

Results: The study involved 926 patients. At 24 months, median nasal polyp score (NPS), nasal obstruction visual analogue scale (VAS), Sino-nasal Outcome Test-22 (SNOT-22), and olfaction improved from baseline (all p < 0.0001). Patients with NPS > 4, and/or SNOT-22 > 30, and/or Sniffin' Sticks Identification Test-16 (SSIT-16) < 12 at 12 months demonstrated improvements in these outcomes over the second year. Overall, 18.7% of patients extended the dupilumab interdose interval to every 4 weeks (q4w). Notably, 91.2% of patients were "good-to-excellent" responders based on EPOS/Euforea criteria. Given the absence of standardized definitions for disease control and remission, we proposed different sets of criteria reporting results from different scenarios. Remission analysis is clinically important as it helps define treatment success and long-term therapeutic goals. Most adverse events were mild-to-moderate; 2.4% of patients discontinued treatment due to safety concerns.

Conclusions: This is the largest real-life study evaluating dupilumab in CRSwNP over 2 years. Dupilumab showed sustained effectiveness, with progressive improvements across all clinical outcomes. Dupilumab tapering did not compromise outcomes; treatment continuation allowed meaningful clinical benefits in late responders. Two-year rates of disease control and remission are clinically relevant, although standardized criteria to assess these outcomes are needed.

Background: Early identification of children at risk of asthma attacks is important for optimizing treatment strategies. We aimed to integrate salivary microbiome and serum inflammatory mediator profiles with asthma attacks history to develop a comprehensive predictive model for future attacks.

Methods: This study contained a discovery (SysPharmPediA) and a replication phase (U-BIOPRED). School-aged children with asthma were classified into at risk and no-risk groups, based on the presence or absence of one or more severe attacks during one-year follow-up. Prediction models were developed using random forest on the training set (70%) with data on past asthma attacks, microbiome composition, serum inflammatory mediator levels, and their combinations and then tested on the rest of the population (30%). Outcomes were replicated in a subset of children with severe asthma from U-BIOPRED.

Results: Complete data were available for 154 children (SysPharmPediA = 121, U-BIOPRED = 33). In discovery, the model based on past attacks resulted in an area under the receiving characteristic curve (AUROCC) ~ 0.7. Models including six salivary bacteria or six inflammatory mediators achieved similar results. The combined model incorporating seven features, past asthma attacks, Capnocytophaga, Corynebacterium, and Cardiobacterium, TIMP-4, VEGF, and MIP-3β achieved the highest accuracy with AUROCC ~0.87. The combined model in the U-BIOPRED limited to available inflammatory mediators (VEGF), and incorporating past asthma attacks, Capnocytophaga, Corynebacterium, and Cardiobacterium, resulted in an AUROCC of 0.84.

Conclusion: Serum inflammatory mediators and salivary microbiome complement asthma attacks history for predicting future attacks. These results highlight the imperative for continued investigation into oral microbiota and its interaction with the immune system.