Journal of Allergy and Clinical Immunology最新文献

英文中文

Transient early blood eosinophil increases do not affect dupilumab’s long-term efficacy in patients with moderate-to-severe asthma 短暂的早期血嗜酸性粒细胞增加不影响Dupilumab在中重度哮喘患者中的长期疗效。

IF 11.2 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2026-02-01 DOI: 10.1016/j.jaci.2025.07.037

Ian D. Pavord MD , Njira L. Lugogo MD , Mario Castro MD , Alberto Papi MD , Arnaud Bourdin MD , Michael E. Wechsler MD , Andréanne Côté MD , Kenneth R. Chapman MD , Changming Xia PhD , Mena Soliman MD , Nami Pandit-Abid PharmD , Juby A. Jacob-Nara MD, DHSc , Harry Sacks MD

Background

Transient increases in blood eosinophil count (BEC) have been observed in dupilumab clinical trials but are rarely associated with clinical symptoms.

Objective

We assessed the effect of early increases in BEC on long-term treatment outcomes.

Methods

Patients aged ≥12 years with moderate-to-severe type 2 asthma from the phase 3 QUEST study (NCT02414854; 52 weeks) who enrolled onto the TRAVERSE open-label extension study (NCT02134028; 96 weeks) were stratified by BEC: with or without ≥2-fold BEC increase any time by week 12 of QUEST, or presence or absence of increased BEC any time during QUEST (defined as <500 cells/μL at baseline but ≥500 cells/μL at any time during QUEST). End points included annualized severe exacerbation rate and change from parent study baseline in prebronchodilator forced expiratory volume in 1 second (FEV₁), 5-item Asthma Control Questionnaire, and type 2 inflammatory biomarkers.

Results

A total of 36.6% of dupilumab-treated patients versus 21.7% of placebo-receiving patients experienced a ≥2-fold BEC change by week 12, while 31.3% versus 28.0% experienced increased BEC any time during QUEST. Dupilumab versus placebo reduced annualized severe exacerbation rate, improved prebronchodilator FEV₁ and questionnaire scores, and reduced biomarkers across subgroups at week 52 of QUEST. Improvements were maintained in all subgroups through week 96 of TRAVERSE.

Conclusions

Dupilumab reduced asthma exacerbations and improved lung function and asthma control up to 148 weeks in patients with uncontrolled moderate-to-severe type 2 asthma irrespective of early transient increases in BEC. Overall safety was consistent with the known dupilumab safety profile.

背景：在dupilumab临床试验中观察到血嗜酸性粒细胞计数（BEC）的短暂增加，但很少与临床症状相关。目的探讨早期BEC升高对长期治疗效果的影响。方法纳入TRAVERSE开放标签扩展研究（NCT02134028, 96周）的3期QUEST研究（NCT02414854, 52周）中年龄≥12岁的中重度2型哮喘患者按BEC分层：在QUEST第12周的任何时间BEC增加/不增加≥2倍，或在QUEST期间任何时间BEC增加/不增加（定义为基线<500细胞/μL，但在QUEST期间任何时间点≥500细胞/μL）。终点包括支气管扩张剂前1秒强迫呼气量（FEV1）、5项哮喘控制问卷（ACQ-5）和2型炎症生物标志物的年化加重率（AER）和双亲研究基线（PSBL）变化。结果36.6%的dupilumumab治疗患者和21.7%的安慰剂治疗患者在第12周出现≥2倍的BEC变化，31.3%和28.0%的患者在QUEST期间任何时间出现BEC增加。与安慰剂相比，Dupilumab降低了AER，改善了支气管扩张剂前FEV1和ACQ-5评分，并降低了QUEST第52周各亚组的生物标志物。所有亚组的改善维持到第96周。结论：dupilumab可减少哮喘发作，改善未控制的中重度2型哮喘患者的肺功能和哮喘控制长达148周，与早期短暂性BEC升高无关。总体安全性与已知的dupilumab安全性一致。

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引用次数: 0

Multiomics insights into retinoic acid–mediated regulation of eosinophils in severe asthma 重度哮喘患者视黄酸介导嗜酸性粒细胞调节的多组学研究

IF 11.2 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2026-02-01 DOI: 10.1016/j.jaci.2025.10.029

Jun Miyata MD, PhD , Keeya Sunata MD, PhD , Hisashi Sasaki MD , Yusuke Kawashima PhD , Yo Otsu MD , Ryuta Onozato MD , Emiko Matsuyama MD , Shinichi Okuzumi MD, PhD , Takao Mochimaru MD, PhD , Katsunori Masaki MD, PhD , Hiroki Kabata MD, PhD , Ryo Konno PhD , Masaki Ishikawa PhD , Yoshinori Hasegawa PhD , Yoshifumi Kimizuka MD, PhD , Makoto Arita PhD , Koichi Fukunaga MD, PhD

Background

Severe asthma is marked by persistent eosinophilic inflammation, but the role of all-trans retinoic acid (ATRA) in eosinophil homeostasis remains unclear.

Objective

This study examined the regulatory role of ATRA in eosinophil function in severe asthma.

Methods

Multiomics analysis (transcriptomics, proteomics, and lipidomics) was conducted on blood eosinophils from healthy participants and patients with severe asthma. The effects of ATRA on eosinophil function were further analyzed by using flow cytometry and quantitative RT-PCR.

Results

Transcriptomic profiling of eosinophils from patients with severe asthma revealed a distinct gene expression signature, with upregulation of the genes GGT5, IL2RA, CCL23, and NOD2 and downregulation of SPRY2 and HIC1. This phenotype was driven by type 2 cytokines (IL-5 and IL-4) and muramyl dipeptide but was counterregulated by ATRA. Proteomic analysis showed increased expression of P-selectin glycoprotein ligand-1 in SA-EOS, which was upregulated by type 2 cytokines and downregulated by ATRA. Lipidomic analysis identified dysregulated 15-lipoxygenase metabolism in SA-EOS, with ATRA selectively inhibiting cysteinyl leukotriene metabolism while sparing the 15-lipoxygenase pathway. Multiomics analysis of eosinophils from ATRA-treated healthy participants revealed specific downregulation of IL1RL1 and IL3RA, reducing responsiveness to IL-33 and IL-3 and distinguishing them from IL-5–induced eosinophils.

Conclusion

These findings highlight the role of ATRA in maintaining eosinophil homeostasis and counterregulating IL-5–driven activation, thus offering insights into potential therapeutic strategies for severe asthma.

重度哮喘以持续的嗜酸性粒细胞炎症为特征，但全反式维甲酸（ATRA）在嗜酸性粒细胞稳态中的作用尚不清楚。目的探讨ATRA对重度哮喘患者嗜酸性粒细胞功能的调节作用。方法采用多组学（转录组学、蛋白质组学和脂质组学）对健康受试者和重度哮喘患者的血嗜酸性粒细胞进行分析。采用流式细胞术和定量RT-PCR分析ATRA对嗜酸性粒细胞功能的影响。结果重度哮喘患者嗜酸性粒细胞的转录组学分析显示，GGT5、IL2RA、CCL23和NOD2基因表达上调，SPRY2和HIC1基因表达下调，具有明显的基因表达特征。这种表型由2型细胞因子（IL-5和IL-4）和muramyl二肽驱动，但被ATRA拮抗。蛋白质组学分析显示，SA-EOS中p -选择素糖蛋白配体1的表达增加，2型细胞因子上调p -选择素糖蛋白配体1，ATRA下调p -选择素糖蛋白配体1的表达。脂质组学分析发现SA-EOS中15-脂氧合酶代谢失调，ATRA选择性抑制半胱氨酸白三烯代谢，同时保留15-脂氧合酶途径。对atra治疗的健康参与者的嗜酸性粒细胞的多组学分析显示，IL1RL1和IL3RA特异性下调，降低了对IL-33和IL-3的反应性，并将它们与il -5诱导的嗜酸性粒细胞区分出来。结论ATRA在维持嗜酸性粒细胞稳态和抑制il -5激活中的作用，为重症哮喘的潜在治疗策略提供了新的思路。

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