重度哮喘中贝那利珠单抗选择性抑制ILC2而非Th2：基线Th2产IL-4与疗效负相关
2026/07/31
摘要
背景：重度哮喘是一种异质性疾病，患者对对生物制剂治疗的反应差异显著。传统生物标志物如外周血嗜酸性粒细胞计数及呼出气一氧化氮（FENO），仅能部分反映这种反应的异质性。
目的：旨在评估2型固有淋巴样细胞（ILC2s）与Th2细胞的细胞因子分泌特征，并探讨其与贝那利珠单抗治疗后临床转归之间的关联。
方法：研究纳入来自东京多中心哮喘研究的70例高T2型重度哮喘患者。采用活细胞成像技术（可实时可视化单个淋巴细胞的细胞因子分泌）评估ILC2s与Th2细胞分泌功能。分别在基线及贝那利珠单抗治疗24周后，定量分析产生IL-4、IL-5及IL-13的细胞频率。临床疗效评估主要采用哮喘控制问卷5（ACQ-5），据此将患者分为应答者与无应答者。研究注册于日本临床试验注册中心（jRCTs031190237）。
结果：在高T2型哮喘患者中，ILC2s与Th2细胞呈现出各异的细胞因子分泌谱，两类细胞群间无明显相关性。贝那利珠单抗治疗可选择性抑制ILC2s产生IL-5与IL-13，而对Th2细胞影响较小。基线期产IL-4的Th2细胞频率较高的患者，接受贝那利珠单抗治疗后临床改善有限。多变量Logistic回归分析显示，在调整外周血嗜酸性粒细胞计数及FENO后，基线产IL-4的Th2细胞频率仍与ACQ-5定义的无应答状态显著相关。
结论：单细胞功能性淋巴细胞谱分析可揭示贝那利珠单抗对固有的和适应性2型淋巴细胞的选择性调节作用，并可为理解重度哮喘治疗反应的异质性提供补充信息。
关键词：贝那利珠单抗；2型先天淋巴样细胞（ILC2s）；Th2细胞；细胞因子；高T2型哮喘
(Misato Irie , Hiroki Kabata et al. Differential responses of group 2 innate lymphoid cells and TH2 cells to benralizumab in severe asthma. J Allergy Clin Immunol. 2026 May 27:S0091-6749(26)00293-9. doi: 10.1016/j.jaci.2026.03.028.)
Abstract
Background: Severe asthma is a heterogeneous disease with variable treatment responses to biologic therapy. Conventional biomarkers, including blood eosinophil counts and fractional exhaled nitric oxide, only partially capture response heterogeneity. Objective: We evaluated the cytokine secretion profiles of group 2 innate lymphoid cells (ILC2s) and TH2 cells and examined their associations with clinical outcomes after benralizumab therapy.
Methods: We analyzed 70 patients with severe type 2-high asthma enrolled onto the multicenter Tokyo Asthma Study. Cytokine secretion by ILC2s and TH2 cells was evaluated by live cell imaging of secretion activity, which enables real-time visualization of cytokine secretion from individual lymphocytes. The frequencies of IL-4-, IL-5-, and IL-13-producing cells were quantified at baseline and after 24 weeks of benralizumab treatment. Clinical responses were primarily assessed by the Asthma Control Questionnaire 5, and patients were classified as experiencing response or not.
Study registration: Japan Registry of Clinical Trials (jRCTs031190237).
Results: In type 2-high asthma, ILC2s and TH2 cells exhibited distinct cytokine secretion profiles with no significant correlation between the two cell populations. Benralizumab selectively suppressed IL-5- and IL-13-producing ILC2s but had little effect on TH2 cells. Patients with higher baseline frequencies of IL-4-producing TH2 cells showed limited clinical improvement after benralizumab therapy. In multivariable logistic regression analysis, baseline IL-4-producing TH2 cell frequency was associated with Asthma Control Questionnaire-defined nonresponse after adjustment for blood eosinophil counts and fractional exhaled nitric oxide.
Conclusions: Single-cell functional lymphocyte profiling identifies distinct innate and adaptive type 2 responses to benralizumab and provides complementary information associated with response heterogeneity in severe asthma.
Keywords: Benralizumab; ILC2; T(H)2 cells; cytokines; type 2–high asthma.
背景：重度哮喘是一种异质性疾病，患者对对生物制剂治疗的反应差异显著。传统生物标志物如外周血嗜酸性粒细胞计数及呼出气一氧化氮（FENO），仅能部分反映这种反应的异质性。
目的：旨在评估2型固有淋巴样细胞（ILC2s）与Th2细胞的细胞因子分泌特征，并探讨其与贝那利珠单抗治疗后临床转归之间的关联。
方法：研究纳入来自东京多中心哮喘研究的70例高T2型重度哮喘患者。采用活细胞成像技术（可实时可视化单个淋巴细胞的细胞因子分泌）评估ILC2s与Th2细胞分泌功能。分别在基线及贝那利珠单抗治疗24周后，定量分析产生IL-4、IL-5及IL-13的细胞频率。临床疗效评估主要采用哮喘控制问卷5（ACQ-5），据此将患者分为应答者与无应答者。研究注册于日本临床试验注册中心（jRCTs031190237）。
结果：在高T2型哮喘患者中，ILC2s与Th2细胞呈现出各异的细胞因子分泌谱，两类细胞群间无明显相关性。贝那利珠单抗治疗可选择性抑制ILC2s产生IL-5与IL-13，而对Th2细胞影响较小。基线期产IL-4的Th2细胞频率较高的患者，接受贝那利珠单抗治疗后临床改善有限。多变量Logistic回归分析显示，在调整外周血嗜酸性粒细胞计数及FENO后，基线产IL-4的Th2细胞频率仍与ACQ-5定义的无应答状态显著相关。
结论：单细胞功能性淋巴细胞谱分析可揭示贝那利珠单抗对固有的和适应性2型淋巴细胞的选择性调节作用，并可为理解重度哮喘治疗反应的异质性提供补充信息。
关键词：贝那利珠单抗；2型先天淋巴样细胞（ILC2s）；Th2细胞；细胞因子；高T2型哮喘
（南方医科大学南方医院 倪钰 凌嘉骏 赵海金）
(Misato Irie , Hiroki Kabata et al. Differential responses of group 2 innate lymphoid cells and TH2 cells to benralizumab in severe asthma. J Allergy Clin Immunol. 2026 May 27:S0091-6749(26)00293-9. doi: 10.1016/j.jaci.2026.03.028.)
Abstract
Background: Severe asthma is a heterogeneous disease with variable treatment responses to biologic therapy. Conventional biomarkers, including blood eosinophil counts and fractional exhaled nitric oxide, only partially capture response heterogeneity. Objective: We evaluated the cytokine secretion profiles of group 2 innate lymphoid cells (ILC2s) and TH2 cells and examined their associations with clinical outcomes after benralizumab therapy.
Methods: We analyzed 70 patients with severe type 2-high asthma enrolled onto the multicenter Tokyo Asthma Study. Cytokine secretion by ILC2s and TH2 cells was evaluated by live cell imaging of secretion activity, which enables real-time visualization of cytokine secretion from individual lymphocytes. The frequencies of IL-4-, IL-5-, and IL-13-producing cells were quantified at baseline and after 24 weeks of benralizumab treatment. Clinical responses were primarily assessed by the Asthma Control Questionnaire 5, and patients were classified as experiencing response or not.
Study registration: Japan Registry of Clinical Trials (jRCTs031190237).
Results: In type 2-high asthma, ILC2s and TH2 cells exhibited distinct cytokine secretion profiles with no significant correlation between the two cell populations. Benralizumab selectively suppressed IL-5- and IL-13-producing ILC2s but had little effect on TH2 cells. Patients with higher baseline frequencies of IL-4-producing TH2 cells showed limited clinical improvement after benralizumab therapy. In multivariable logistic regression analysis, baseline IL-4-producing TH2 cell frequency was associated with Asthma Control Questionnaire-defined nonresponse after adjustment for blood eosinophil counts and fractional exhaled nitric oxide.
Conclusions: Single-cell functional lymphocyte profiling identifies distinct innate and adaptive type 2 responses to benralizumab and provides complementary information associated with response heterogeneity in severe asthma.
Keywords: Benralizumab; ILC2; T(H)2 cells; cytokines; type 2–high asthma.
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重度哮喘中纤毛相关分子候选基因的鉴定与验证
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FENO作为无哮喘患者多重食物过敏潜在生物标志物的应用价值
