Pseudomonas aeruginosa infection, but not mono or dual-combination CFTR modulator therapy affects circulating regulatory T cells in an adult population with cystic fibrosis

Westhölter, Dirk; Beckert, Hendrik; Straßburg, Svenja; Welsner, Matthias; Sutharsan, Sivagurunathan; Taube, Christian; Reuter, Sebastian

doi:10.1016/j.jcf.2021.05.001

Cited by 13 publications

(16 citation statements)

References 28 publications

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“…Whole blood samples were collected at T0, T1 and T2 and prepared as previously described ( 18 ). In brief, 12 mL of whole blood was collected from each participant and processed within four hours after collection.…”

Section: Methodsmentioning

confidence: 99%

“…Antibodies and the gating strategy used to identify T cell subsets have been described previously and were adapted from Rühle et al. ( Figure S1 ; 18 , 20 ). Tregs were defined as CD4 + CD127 low CD25 + cells and further characterized as CD39 + “stable” Tregs ( Figure S1 ).…”

Section: Methodsmentioning

confidence: 99%

“…However, these studies involve only a small number of participants and conflicting data exist ( 17 ). We previously compared PwCF receiving versus not receiving mono or dual combination CFTR modulators in a cross-sectional study and did not find any difference in either lymphocyte subsets including Tregs or cytokines in peripheral blood ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy

Westhölter

Raspe²,

Uebner³

et al. 2023

Front. Immunol.

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IntroductionCystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF.MethodsPeripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry.ResultsElexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (–50.2%, p<0.001).ConclusionTreatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy

Westhölter

Raspe²,

Uebner³

et al. 2023

Front. Immunol.

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“…Hector and colleagues found a negative correlation between Tregs levels in blood and bronchoalveolar lavage fluid, and Pseudomonas infection in children with CF [ 52 ]. The same group treated human peripheral blood mononuclear cells (PBMCs) with cell-free supernatants from different P. aeruginosa strains and showed that particularly virulent and flagellin-deficient strains seem to decrease Tregs in CF [ 52 , 53 ]. In adult CF patients, chronic P. aeruginosa lung infection was associated with impaired proportion of peripheral Tregs.…”

Section: Airway Infections In Cystic Fibrosismentioning

confidence: 99%

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

Saluzzo

Riberi

Messore

et al. 2022

Cells

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Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed.

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“…Dirk Westhölter (Essen, Germany) outlined immunophenotyping data revealing that circulating regulatory T-cells are impaired in patients with cystic fibrosis and chronic P. aeruginosa infection [ 78 ]. Patients with non-cystic fibrosis bronchiectasis showed higher levels of systemic of CD39 regulatory T-cells (stable under inflammatory conditions) compared to cystic fibrosis.…”

Section: Adult Cystic Fibrosismentioning

confidence: 99%

ERS International Congress 2021: highlights from the Respiratory Infections Assembly

Meldrum

Belchamber

Chichirelo-Konstantynovych

et al. 2022

ERJ Open Res

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The European Respiratory Society Annual Congress 2021 took place virtually for the second year running due to the coronavirus pandemic. The congress programme featured more than 400 sessions and 3000 abstract presentations, covering the entire respiratory science and medicine field. In this article, Early Career Members of the Respiratory Infections Assembly summarise a selection of sessions across a broad range of topics, including presentations on bronchiectasis, non-tuberculosis mycobacteria, tuberculosis, cystic fibrosis and COVID-19.

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Pseudomonas aeruginosa infection, but not mono or dual-combination CFTR modulator therapy affects circulating regulatory T cells in an adult population with cystic fibrosis

Cited by 13 publications

References 28 publications

Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy

Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

ERS International Congress 2021: highlights from the Respiratory Infections Assembly

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