title: Bronchiolitis obliterans syndrome is associated with increased peripheral blood natural killer and natural killer T-like granzymes, perforin, and T-helper-type 1 pro-inflammatory cytokines.
abstract: BACKGROUND
  We previously showed that bronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T-cell pro-inflammatory cytokines and granzyme B. We recently showed that natural killer (NK) T (NKT)-like cells are a major source of pro-inflammatory cytokines and granzymes in the blood of stable lung transplant patients. NK cells also produce these pro-inflammatory mediators, and we hypothesized that BOS may be associated with lack of immunosuppression of these pro-inflammatory mediators in NK and NKT-like cells.
  
  
  METHODS
  Granzyme, perforin, and intracellular cytokine profiles from stable transplant recipients, patients with evidence of BOS, and healthy controls were determined using multiparameter flow cytometry.
  
  
  RESULTS
  The percentage of NK cells expressing granzymes and perforin was significantly increased in BOS patients compared with stable patients and in stable patients compared with controls (89% ± 13%, 69% ± 12%, 33% ± 14% for NK and 35% ± 19%, 12% ± 15%, and 2% ± 3% for NKT-like granzyme B producing cells for BOS, stable patients and controls, respectively). There was an increase in the percentage of NK and NKT-like cells producing interferon (IFN)-γ and tumor necrosis factor (TNF)-α in BOS compared with stable patients (36% ± 16% and 10% ± 4% for NK and 32% ± 13% and 17% ± 8% for NKT-like IFN-γ producing cells for BOS and stable patients, respectively). There was a significant correlation between increased NK IFN-γ and TNF-α and values of forced expiratory volume in 1 second.
  
  
  CONCLUSIONS
  BOS is associated with increased peripheral blood NK and NKT-like cells expressing granzymes, perforin, and Th1 pro-inflammatory cytokines. These cells may migrate to the lungs and have an impact in airway damage in BOS. Therapeutic targeting of these pro-inflammatory mediators and monitoring response longitudinally using this assay may reduce BOS.
authors: Lung Research, Hanson Institute, Royal Adelaide Hospital, Adelaide, SA 5006, Australia. greg.hodge@health.sa.gov.au
authors: Greg
authors: G
authors: Hodge
authors: Sandra
authors: S
authors: Hodge
authors: Chien-Li
authors: CL
authors: Holmes-Liew
authors: Paul N
authors: PN
authors: Reynolds
authors: Mark
authors: M
authors: Holmes
mesh_terms: D000328:Adult; D001989:Bronchiolitis Obliterans / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000378:metabolism* / Q000473:pathology; D054353:Perforin / Q000378:metabolism*; D013577:Syndrome; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes