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Alterations in blood leukocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor.

ABSTRACT: Ivacaftor improves clinical outcome by potentiation of mutant G551D CFTR. Due to the presence of CFTR in monocytes and polymorphonuclear neutrophils (PMNs), we hypothesized that ivacaftor may impact leukocyte activation.We examined blood leukocytes from G551D CF subjects prior to and at one and six months after receiving ivacaftor. Blood leukocytes from ivacaftor-naïve G551D, F508del, and healthy controls were also treated with ivacaftor ex vivo to assess mutation-specific effects.Compared to healthy controls, G551D CF subjects had significantly higher expression of active CD11b on PMNs and of CD63 on monocytes, which were normalized by in vivo ivacaftor treatment. Ex vivo exposure to ivacaftor of blood cells from G551D, but not F508del and healthy subjects, resulted in changes in CXCR2 and CD16 expression on PMNs.In vivo and ex vivo exposure of G551D CF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation.

SUBMITTER: Bratcher PE

PROVIDER: S-EPMC4567518 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Alterations in blood leukocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor.

Bratcher Preston E PE Rowe Steven M SM Reeves Ginger G Roberts Tambra T Szul Tomasz T Harris William T WT Tirouvanziam Rabindra R Gaggar Amit A

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 20150311 1

<h4>Background</h4>Ivacaftor improves clinical outcome by potentiation of mutant G551D CFTR. Due to the presence of CFTR in monocytes and polymorphonuclear neutrophils (PMNs), we hypothesized that ivacaftor may impact leukocyte activation.<h4>Methods</h4>We examined blood leukocytes from G551D CF subjects prior to and at one and six months after receiving ivacaftor. Blood leukocytes from ivacaftor-naïve G551D, F508del, and healthy controls were also treated with ivacaftor ex vivo to assess mutat ...[more]

PMID: 25769931

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Project description:Rationale: Modulation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein improves clinical outcomes in patients with CF and specific CFTR genetic mutations. It remains unclear how improving CFTR function modifies existing airway infection and inflammation.Objectives: To compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment.Methods: The study included 31 people with CF, ages 10 years and older, with at least one G551D CFTR allele and an forced expiratory volume in 1 second (FEV1) of 40% predicted or greater who were enrolled in the GOAL (G551D Observational) study. Sputum samples were collected either by induction (n?=?14) or by spontaneous expectoration (n?=?17) before and 6 months after initiation of ivacaftor. Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined.Results: The cohort that spontaneously expectorated sputum had a lower FEV1, a higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction. Although the overall cohort experienced significant improvements in FEV1 and reductions in sweat chloride, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients.Conclusions: In this multicenter cohort, 6 months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and antiinflammatory treatments will still be needed to manage airway disease in patients with CF treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

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Alterations in blood leukocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor.

Publications

Alterations in blood leukocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor.

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