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

Abstract

Background 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. Methods 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. Results 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. Conclusions In vivo and ex vivo exposure of G551D CF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation.

Neutrophils in cystic fibrosis

“…Collectively, CFTR function in neutrophils has been associated with granule exocytosis and phagocytosis, as well as sustained neutrophilic lung inflammation in response to infection (Painter et al, 2006;Bonfield et al, 2012;Ng et al, 2014;Pohl et al, 2014). Intriguingly, the CFTR potentiator ivacaftor was found to modulate leukocyte activation in CF patients (Pohl et al, 2014;Bratcher et al, 2016). In summary, the paradigms of neutrophils in CF are constantly evolving and become more complex, emphasizing the need for further basic studies to better understand this seemingly simple, yet highly versatile innate immune cell.…”

Cystic Fibrosis Lung Immunity: The Role of the Macrophage

“…As prospective for the future, an effective, long-term therapy for CF should also modulate monocytes/MΦs function, as also suggested by studies in patients treated with ivacftor 34–36 .…”

“…Further, treatments that improve clinical parameters in patients with CF, such as the antibiotic azithromycin, have been found to reduce the pro-inflammatory phenotype in AM 33 , and peripheral blood monocytes respond to CFTR potentiator therapy (ivacaftor) in patients carrying G551D mutation 34, 35, 36 .…”

CFTR‐dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy

“…However, emerging data are pointing out to the regulatory role of CFTR in monocyte and macrophage function, including optimal phagocytosis and killing of Pseudomonas aeruginosa , pro‐inflammatory responses, and adhesion to endothelium while another study showed that ivacaftor treatment normalized active CD11b on neutrophils and CD63 on monocytes …”