Maher Rosemary E, Cytlak-Chaudhuri Urszula M, Aleem Saad, Barry Peter, Brice Daniel Paul, Caamaño Gutiérrez Eva, Driver Kimberley, Emmott Edward, Rothwell Alexander, Smith Emily, Travis Mark, Lee Dave, McNamara Paul Stephen, Waller Ian, Smith Jaclyn Ann, Jones Andrew, Lord Robert W
Centre for Proteome Research, Department of Biochemistry & Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
Lydia Becker Institute for Immunology and Inflammation, University of Manchester, Manchester, UK.
Thorax. 2025 Aug 15;80(9):604-615. doi: 10.1136/thorax-2024-222242.
Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis (CF) established on elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy.
We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age-matched healthy controls.
Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift towards an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared with healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function.
Patients with CF showed evidence of persisting systemic inflammation despite ETI therapy, which may have long-term potentially adverse effects on respiratory and other organ systems.
尽管在临床方面有显著改善，但有证据表明，接受依列卡福/替扎卡福/依伐卡福（ETI）治疗的囊性纤维化（CF）患者存在持续的气道炎症。由于CF是一种多系统疾病，全身免疫特征可以反映肺部和其他器官的局部炎症。了解ETI治疗后的全身炎症可能会揭示重要的转化见解。本研究旨在分析全身炎症变化，并将这些变化与ETI治疗所观察到的已充分记录的改善情况相关联。
我们对57名开始ETI治疗的CF受试者进行了一项单中心纵向研究。所有参与者均为苯丙氨酸508缺失纯合子或苯丙氨酸508缺失/功能最低者。在开始ETI治疗前及治疗开始后3 - 12个月采集血样。分析包括基于质谱的蛋白质组学、多重免疫测定以及对外周免疫细胞计数和表型的流式细胞术分析。对照样本由29名年龄匹配的健康对照者提供。
ETI治疗后全身炎症减轻；然而，免疫特征仍与健康对照者不同。ETI降低了中性粒细胞计数，并与更成熟、炎症性更低的表型相关，同时向与CD206表达增加相关的免疫消退状态转变。已知影响中性粒细胞水平的细胞因子随治疗而减少。尽管进行了ETI治疗，但与健康对照者相比，中性粒细胞和单核细胞计数仍升高。ETI相关的全身炎症改善与肺功能之间没有明显关联。
CF患者尽管接受了ETI治疗，但仍有持续全身炎症的证据，这可能对呼吸和其他器官系统产生长期潜在不良影响。
