title: Histone deacetylase 2 is decreased in peripheral blood pro-inflammatory CD8+ T and NKT-like lymphocytes following lung transplant.
abstract: Immunosuppression therapy following lung transplantation fails to prevent chronic rejection in many patients, which is associated with lack of suppression of cytotoxic mediators and pro-inflammatory cytokines in peripheral blood T and natural killer T (NKT)-like cells. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) upregulate/downregulate pro-inflammatory gene expression, respectively; however, differences in the activity of these enzymes following lung transplant are unknown. We hypothesized decreased HDAC2 expression and increased HAT expression in pro-inflammatory lymphocytes following lung transplant.
  
  
  
  Blood was collected from 18 stable lung transplant patients and 10 healthy age-matched controls. Intracellular pro-inflammatory cytokines and HAT/HDAC2 expression were determined in lymphocyte subsets following culture using flow cytometry.
  
  
  
  A loss of HDAC2 in cluster of differentiation (CD) 8+ T and NKT-like cells in transplant patients compared with controls was noted (CD8+ T: 28 ± 10 (45 ± 10), CD8+NKT-like: 30 ± 13 (54 ± 16) (mean ± SD transplant) (control)). Loss of HDAC2 was associated with an increased percentage of CD8+ T and NKT-like cells expressing perforin, granzyme b, interferon gamma (IFN-γ) and TNF-α (no change in HAT expression in any lymphocyte subset). There was a negative correlation between loss of HDAC2 expression by CD8+ T cells with cumulative dose of prednisolone and time post-transplant. Treatment with 10 mg/L theophylline + 1 µmol/L prednisolone or 2.5 ng/mL cyclosporine A synergistically upregulated HDAC2 and inhibited IFN-γ and TNF-α production by CD8+ T and NKT-like lymphocytes.
  
  
  
  HDAC2 is decreased in CD8+ T and NKT-like pro-inflammatory lymphocytes following lung transplant. Treatment options that increase HDAC2 may improve graft survival.
authors.affiliation: Lung Research, Hanson Institute, Adelaide, South Australia, Australia.|Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Hodge
authors.affiliation: Lung Research, Hanson Institute, Adelaide, South Australia, Australia.|Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hodge
authors.affiliation: Lung Research, Hanson Institute, Adelaide, South Australia, Australia.|Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|South Australian Lung Transplant Service, Adelaide, South Australia, Australia.
authors.forename: Chien-Li
authors.initials: CL
authors.lastname: Holmes-Liew
authors.affiliation: Lung Research, Hanson Institute, Adelaide, South Australia, Australia.|Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
authors.affiliation: Lung Research, Hanson Institute, Adelaide, South Australia, Australia.|Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.|South Australian Lung Transplant Service, Adelaide, South Australia, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Holmes
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D006085:Graft Survival / Q000276:immunology; D053804:Granzymes / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects / Q000379:methods; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D056464:Histone Deacetylase 2
keywords: cluster of differentiation 8+ T and natural killer T-like; histone deacetylase 2; pro-inflammatory lymphocytes; theophylline