Observational Study

. 2016 Jan;15(1):67-73.

doi: 10.1016/j.jcf.2015.02.010. Epub 2015 Mar 11.

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

Preston E Bratcher¹, Steven M Rowe², Ginger Reeves³, Tambra Roberts⁴, Tomasz Szul⁵, William T Harris⁶, Rabindra Tirouvanziam⁷, Amit Gaggar⁸

Affiliations

¹ Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: bratcher@qiuluzeuv.cn.
² Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; University of Alabama at Birmingham, UAB Lung Health Center, 526 20th Street South, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA; Department of Cell, Developmental, and Integrative Biology, THT 926, 1720 2nd Avenue South, Birmingham, AL 35294, USA. Electronic address: smrowe@qiuluzeuv.cn.
³ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA. Electronic address: greeves@qiuluzeuv.cn.
⁴ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA. Electronic address: troberts@qiuluzeuv.cn.
⁵ Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: szultom@qiuluzeuv.cn.
⁶ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: tharris@qiuluzeuv.cn.
⁷ Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics, Emory University, 2015 Uppergate Drive, Room 344, Atlanta, GA 30322, USA; Center for Cystic Fibrosis and Airway Disease Research, Children's Healthcare of Atlanta, 2015 Uppergate Drive, Room 344, Atlanta, GA 30322, USA. Electronic address: tirouvanziam@qiuluzeuv.cn.
⁸ Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; University of Alabama at Birmingham, UAB Lung Health Center, 526 20th Street South, Birmingham, AL 35294, USA; Medicine Service, United States Department of Veterans Affairs Medical Center, 700 19th Street South, Birmingham, AL 35233, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: agaggar1@qiuluzeuv.cn.

Observational Study

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

Preston E Bratcher et al. J Cyst Fibros. 2016 Jan.

. 2016 Jan;15(1):67-73.

doi: 10.1016/j.jcf.2015.02.010. Epub 2015 Mar 11.

Authors (VSports注册入口)

Preston E Bratcher¹, Steven M Rowe², Ginger Reeves³, Tambra Roberts⁴, Tomasz Szul⁵, William T Harris⁶, Rabindra Tirouvanziam⁷, Amit Gaggar⁸

"V体育平台登录" Affiliations

¹ Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: bratcher@qiuluzeuv.cn.
² Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; University of Alabama at Birmingham, UAB Lung Health Center, 526 20th Street South, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA; Department of Cell, Developmental, and Integrative Biology, THT 926, 1720 2nd Avenue South, Birmingham, AL 35294, USA. Electronic address: smrowe@qiuluzeuv.cn.
³ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA. Electronic address: greeves@qiuluzeuv.cn.
⁴ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA. Electronic address: troberts@qiuluzeuv.cn.
⁵ Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: szultom@qiuluzeuv.cn.
⁶ Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics at Children's of Alabama, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: tharris@qiuluzeuv.cn.
⁷ Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA; Department of Pediatrics, Emory University, 2015 Uppergate Drive, Room 344, Atlanta, GA 30322, USA; Center for Cystic Fibrosis and Airway Disease Research, Children's Healthcare of Atlanta, 2015 Uppergate Drive, Room 344, Atlanta, GA 30322, USA. Electronic address: tirouvanziam@qiuluzeuv.cn.
⁸ Department of Medicine and Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 424 THT, 1900 University Blvd, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 790, 1918 University Blvd, Birmingham, AL 35294, USA; University of Alabama at Birmingham, UAB Lung Health Center, 526 20th Street South, Birmingham, AL 35294, USA; Medicine Service, United States Department of Veterans Affairs Medical Center, 700 19th Street South, Birmingham, AL 35233, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, MCLM 760, 1918 University Blvd, Birmingham, AL 35294, USA. Electronic address: agaggar1@qiuluzeuv.cn.

PMID: 25769931
PMCID: PMC4567518
DOI: 10.1016/j.jcf.2015.02.010

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. VSports手机版.

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 V体育安卓版. .

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 V体育ios版. .

Conclusions: In vivo and ex vivo exposure of G551D CF leukocytes to ivacaftor resulted in an altered activation profile, suggesting mutation-specific leukocyte modulation. VSports最新版本.

Keywords: Blood; CFTR; G551D; Ivacaftor; Leukocyte; VX-770 V体育平台登录. .

Published by Elsevier B.V.

PubMed Disclaimer

Figures

**Figure 1. Surface marker expression and intracellular caspase-1 activity in peripheral blood leukocytes**
Flow cytometry was used to analyze the activity of caspase-1 and surface expression of CD63 and activated CD11b on PMNs and monocytes. Cells from patients were analyzed at enrollment in the study (V1), one month post enrollment (V3), and six months post enrollment (V5). Additionally, cells from healthy controls (HC) were also analyzed. For these plots, samples from the same patient are connected by a dotted line, and a solid horizontal line was drawn at the mean for each group. An asterisk (*) denotes a significant difference compared to the healthy control group by Kruskal-Wallis with Dunns Multiple Comparisons test.

**Figure 2. Changes in surface marker expression on peripheral blood leukocytes stimulated with PMA**
Flow cytometry was used to analyze the surface expression of activated CD11b and CXCR2 in PMA-stimulated PMNs and monocytes. For these plots, the line represents the mean, and a dotted line is used to connect values from the same patient. The mean change in activated CD11b on PMNs for the healthy control (HC) group is 21.5 fold.

**Figure 3. Effects of *ex vivo* ivacaftor treatment on peripheral blood PMNs**
A: Histograms of surface CD16 (top row), CXCR2 (middle row), and CD63 (bottom row) expression on PMNs treated with either Ivacaftor (black line) or vehicle (DMSO, shaded gray) from representative G551D, F508del and healthy control subjects. B: Box plots illustrating the changes in CD16 and CXCR2 expression in PMNs by Ivacaftor treatment in the three groups. C: Box plots illustrating the difference in CD16^int and CXCR2^int subsets induced among blood PMNs by Ivacaftor treatment. CD16^int and CXCR2^int subsets were defined by gates set below the lower 99% percentile in matched DMSO-treated PMNs. The G551D group showed a significant difference compared to other groups, as tested using the Kruskal-Wallis method (for CD16, p = 0.0376 and for CXCR2, p = 0.0302). The whiskers in all plots represent the minimum and maximum values.

See this image and copyright information in PMC

References

1. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256(5058):774–779. - PubMed
1. Quinton PM. Cystic fibrosis: lessons from the sweat gland. Physiology (Bethesda) 2007;22:212–225. - PubMed
1. Bradbury NA, Jilling T, Berta G, Sorscher EJ, Bridges RJ, Kirk KL. Regulation of plasma membrane recycling by CFTR. Science. 1992;256(5056):530–532. - PubMed
1. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992–2001. - PubMed
1. Ratner D, Mueller C. Immune responses in cystic fibrosis: are they intrinsically defective? Am J Respir Cell Mol Biol. 2012;46(6):715–722. - PubMed

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

Affiliations

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

Authors (VSports注册入口)

"V体育平台登录" Affiliations

Abstract

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References

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