Tezepelumab可降低气道上皮细胞IL-33和T2炎症，以应对哮喘患者的病毒刺激
2023/11/23
摘要
背景：呼吸道病毒感染是哮喘恶化的主要诱因。Tezepelumab是一种抗TSLP单克隆抗体，可减少哮喘患者的恶化，但阻断TSLP对宿主上皮抵抗力和对病毒感染耐受性的影响尚不清楚。
目的：研究阻断哮喘患者TSLP对宿主抵抗力（IFNβ、IFNλ和病毒载量）以及对病毒攻击的气道上皮炎症反应的影响。
方法：从未控制哮喘患者中获取支气管肺泡灌洗液（BALF，n=39）和支气管上皮细胞（BECs），分别在12周的tezepelumab治疗（n=13）或安慰剂（n=13）前后进行。体外培养BECs，并暴露于病毒感染模拟物Poly(I:C)或感染鼻病毒（RV）。在刺激前后，通过RT-qPCR和多重ELISA分析醛固酮、T2-和促炎细胞因子、IFNβ、IFNλ和病毒载量。
结果：在12周的tezepelumab治疗后，未受刺激的BEC中IL-33的表达和BALF中的IL-33蛋白水平降低。此外，tezepelumab治疗后的BEC中，IL-33基因和蛋白水平降低，而TSLP基因表达不受影响。tezepelumab还降低了Ploy（I：C）诱导的BEC中IL-4、IL-13和IL-17A的释放，而IFNβ和IFNλ的表达和病毒载量没有变化。
结论：在哮喘中，体内用tezepelumab阻断TSLP，可减少气道上皮炎症反应，包括IL-33和T2细胞因子对病毒攻击的反应，而不会影响抗病毒宿主抵抗力。我们的结果表明，阻断TSLP可稳定支气管上皮对呼吸道病毒的免疫反应。
Tezepelumab decreases airway epithelial IL-33 and T2-inflammation in response to viral stimulation in patients with asthma
A Sverrild, S Cerps, J J Nieto-Fontarigo, S Ramu, M Hvidtfeldt, M Menzel, J Kearley, J M Griffiths, J R Parnes, C Porsbjerg, L Uller
Abstract
Background: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti-TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known.
Aim: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNβ, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge.
Methods: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2- and pro-inflammatory cytokines, IFNβ IFNλ, and viral load were analyzed by RT-qPCR and multiplex ELISA before and after stimulation.
Results: IL-33 expression in unstimulated BECs and IL-33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL-33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)-induced IL-4, IL-13, and IL-17A release from BECs was also reduced with tezepelumab whereas IFNβ and IFNλ expression and viral load were unchanged.
Conclusion: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL-33 and T2 cytokines to viral challenge without affecting anti-viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses.
背景：呼吸道病毒感染是哮喘恶化的主要诱因。Tezepelumab是一种抗TSLP单克隆抗体，可减少哮喘患者的恶化，但阻断TSLP对宿主上皮抵抗力和对病毒感染耐受性的影响尚不清楚。
目的：研究阻断哮喘患者TSLP对宿主抵抗力（IFNβ、IFNλ和病毒载量）以及对病毒攻击的气道上皮炎症反应的影响。
方法：从未控制哮喘患者中获取支气管肺泡灌洗液（BALF，n=39）和支气管上皮细胞（BECs），分别在12周的tezepelumab治疗（n=13）或安慰剂（n=13）前后进行。体外培养BECs，并暴露于病毒感染模拟物Poly(I:C)或感染鼻病毒（RV）。在刺激前后，通过RT-qPCR和多重ELISA分析醛固酮、T2-和促炎细胞因子、IFNβ、IFNλ和病毒载量。
结果：在12周的tezepelumab治疗后，未受刺激的BEC中IL-33的表达和BALF中的IL-33蛋白水平降低。此外，tezepelumab治疗后的BEC中，IL-33基因和蛋白水平降低，而TSLP基因表达不受影响。tezepelumab还降低了Ploy（I：C）诱导的BEC中IL-4、IL-13和IL-17A的释放，而IFNβ和IFNλ的表达和病毒载量没有变化。
结论：在哮喘中，体内用tezepelumab阻断TSLP，可减少气道上皮炎症反应，包括IL-33和T2细胞因子对病毒攻击的反应，而不会影响抗病毒宿主抵抗力。我们的结果表明，阻断TSLP可稳定支气管上皮对呼吸道病毒的免疫反应。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Allergy. 2023 Oct 17. doi: 10.1111/all.15918.)
(Allergy. 2023 Oct 17. doi: 10.1111/all.15918.)
Tezepelumab decreases airway epithelial IL-33 and T2-inflammation in response to viral stimulation in patients with asthma
A Sverrild, S Cerps, J J Nieto-Fontarigo, S Ramu, M Hvidtfeldt, M Menzel, J Kearley, J M Griffiths, J R Parnes, C Porsbjerg, L Uller
Abstract
Background: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti-TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known.
Aim: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNβ, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge.
Methods: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2- and pro-inflammatory cytokines, IFNβ IFNλ, and viral load were analyzed by RT-qPCR and multiplex ELISA before and after stimulation.
Results: IL-33 expression in unstimulated BECs and IL-33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL-33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)-induced IL-4, IL-13, and IL-17A release from BECs was also reduced with tezepelumab whereas IFNβ and IFNλ expression and viral load were unchanged.
Conclusion: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL-33 and T2 cytokines to viral challenge without affecting anti-viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses.
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