气道蛋白质组学在美泊利珠单抗治疗哮喘中显示出广泛的残留抗炎作用
2024/08/28
摘要
背景：美泊利珠单抗是一种治疗重度嗜酸性哮喘(SEA)的抗白细胞介素-5单克隆抗体，可减少哮喘加重。美泊利珠单抗的残留气道炎症可能导致持续急性加重。口服皮质类固醇仍然是治疗这些残留加重的主要方法。
目的：本研究旨在探索美泊利珠单抗治疗后气道炎症的皮质激素反应性，以发现IL-5途径之外的潜在可治疗炎症机制。
方法：MAPLE试验是一项多中心、随机、双盲、安慰剂对照、交叉研究，对27例美泊利珠单抗治疗SEA的患者进行稳定状态下大剂量口服强的松龙治疗2周。我们使用高通量Olink®蛋白质组学分析了MAPLE试验中成对的痰(n=16)和血浆(n=25)样本。我们还使用ELISA分析了其他痰蛋白。
结果：在接受美泊利珠单抗治疗的患者中，强的松龙显著下调了与2型炎症和趋化性相关的痰蛋白，包括IL-4、IL-5、IL-13、CCL24、CCL26、EDN、CCL17、CCL22、OX40受体、FCER2和ST2受体。强的松龙还下调细胞粘附分子、前列腺素合成酶、肥大细胞胰蛋白酶、MMP1、MMP12和神经免疫介质。中性粒细胞通路上调。血浆中2型蛋白也下调，与IL-12、IFN-γ和IP-10联合下调。IL-10和双调节蛋白上调。
结论：在稳定状态下，强的松龙在美泊利珠单抗的基础上具有广泛的抗炎作用。这些影响是不均匀的，可能与残留恶化有临床相关性。
Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma
Imran Howell, Freda Yang, Vanessa Brown, Jennifer Cane, Emanuele Marchi, Adnan Azim, John Busby, Pamela J McDowell, Sarah E Diver, Catherine Borg, Liam G Heaney, Ian D Pavord, Christopher E Brightling, Rekha Chaudhuri, Timothy S C Hinks
Abstract
Background: Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations.
Objective: Our study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway.
Method: The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA.
Results: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated.
Conclusion: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.
背景：美泊利珠单抗是一种治疗重度嗜酸性哮喘(SEA)的抗白细胞介素-5单克隆抗体，可减少哮喘加重。美泊利珠单抗的残留气道炎症可能导致持续急性加重。口服皮质类固醇仍然是治疗这些残留加重的主要方法。
目的：本研究旨在探索美泊利珠单抗治疗后气道炎症的皮质激素反应性，以发现IL-5途径之外的潜在可治疗炎症机制。
方法：MAPLE试验是一项多中心、随机、双盲、安慰剂对照、交叉研究，对27例美泊利珠单抗治疗SEA的患者进行稳定状态下大剂量口服强的松龙治疗2周。我们使用高通量Olink®蛋白质组学分析了MAPLE试验中成对的痰(n=16)和血浆(n=25)样本。我们还使用ELISA分析了其他痰蛋白。
结果：在接受美泊利珠单抗治疗的患者中，强的松龙显著下调了与2型炎症和趋化性相关的痰蛋白，包括IL-4、IL-5、IL-13、CCL24、CCL26、EDN、CCL17、CCL22、OX40受体、FCER2和ST2受体。强的松龙还下调细胞粘附分子、前列腺素合成酶、肥大细胞胰蛋白酶、MMP1、MMP12和神经免疫介质。中性粒细胞通路上调。血浆中2型蛋白也下调，与IL-12、IFN-γ和IP-10联合下调。IL-10和双调节蛋白上调。
结论：在稳定状态下，强的松龙在美泊利珠单抗的基础上具有广泛的抗炎作用。这些影响是不均匀的，可能与残留恶化有临床相关性。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Aug 1:S0091-6749(24)00777-2. doi: 10.1016/j.jaci.2024.07.020.)
(J Allergy Clin Immunol. 2024 Aug 1:S0091-6749(24)00777-2. doi: 10.1016/j.jaci.2024.07.020.)
Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma
Imran Howell, Freda Yang, Vanessa Brown, Jennifer Cane, Emanuele Marchi, Adnan Azim, John Busby, Pamela J McDowell, Sarah E Diver, Catherine Borg, Liam G Heaney, Ian D Pavord, Christopher E Brightling, Rekha Chaudhuri, Timothy S C Hinks
Abstract
Background: Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations.
Objective: Our study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway.
Method: The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA.
Results: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated.
Conclusion: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.
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在特异性吸入激发试验期间持续吸入皮质类固醇治疗对诊断职业性哮喘的影响
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在严重哮喘中滴定抗IL5生物制剂（OPTIMAL）：一项开放标签随机对照试验
