title: Lymphocyte senescence in COPD is associated with loss of glucocorticoid receptor expression by pro-inflammatory/cytotoxic lymphocytes.
abstract: BACKGROUND
  Glucocorticoid (GC) resistance is a major barrier in COPD treatment. We have shown increased expression of the drug efflux pump, Pgp1 in cytotoxic/pro-inflammatory lymphocytes in COPD. Loss of lymphocyte co-stimulatory molecule CD28 (lymphocyte senescence) was associated with a further increase in their pro-inflammatory/cytotoxic potential and resistance to GC. We hypothesized that lymphocyte senescence and increased Pgp1 are also associated with down-regulation of the GC receptor (GCR).
  
  
  METHODS
  Blood was collected from 10 COPD and 10 healthy aged-matched controls. Flow cytometry was applied to assess intracellular pro-inflammatory cytokines, CD28, Pgp1, GCR, steroid binding and relative cytoplasm/nuclear GCR by CD28+ and CD28null T, NKT-like cells. GCR localization was confirmed by fluorescent microscopy.
  
  
  RESULTS
  COPD was associated with increased numbers of CD28nullCD8+ T and NKT-like cells. Loss of CD28 was associated with an increased percentage of T and NKT-like cells producing IFNγ or TNFα and associated with a loss of GCR and Dex-Fluor staining but unchanged Pgp1. There was a significant loss of GCR in CD8 + CD28null compared with CD8 + CD28+ T and NKT-like cells from both COPD and controls (eg, mean ± SEM 8 ± 3% GCR + CD8 + CD28null T-cells vs 49 ± 5% GCR + CD8 + CD28+ T-cells in COPD). There was a significant negative correlation between GCR expression and IFNγ and TNFα production by T and NKT-like cells(eg, COPD: T-cell IFNγ R = -.615; ) and with FEV1 in COPD (R = -.777).
  
  
  CONCLUSIONS
  COPD is associated with loss of GCR in senescent CD28null and NKT-like cells suggesting alternative treatment options to GC are required to inhibit these pro-inflammatory/cytotoxic cells.
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. greg.hodge@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia. greg.hodge@health.sa.gov.au.
authors.forename: Greg
authors.initials: G
authors.lastname: Hodge
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. hubertus.jersmann@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia. hubertus.jersmann@health.sa.gov.au.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Jersmann
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. hai.tran@health.sa.gov.au.
authors.forename: Hai B
authors.initials: HB
authors.lastname: Tran
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. mark.holmes@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia. mark.holmes@health.sa.gov.au.
authors.forename: Mark
authors.initials: M
authors.lastname: Holmes
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. paul.reynolds@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia. paul.reynolds@health.sa.gov.au.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. sandra.hodge@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia. sandra.hodge@health.sa.gov.au.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hodge
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000097:blood; D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D016922:Cellular Senescence; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D015536:Down-Regulation; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000097:blood / Q000276:immunology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018106:CD28 Antigens; D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D011965:Receptors, Glucocorticoid