title: Targeting peripheral blood pro-inflammatory cytotoxic lymphocytes by inhibiting CD137 expression: novel potential treatment for COPD.
abstract: BACKGROUND
  We have shown that chronic obstructive pulmonary disease (COPD) is associated with increased production of pro-inflammatory cytokines and the cytotoxic mediator, granzyme B by peripheral blood steroid resistant CD28nullCD137 + CD8+ T cells and granzyme B by NKT-like and NK cells. We hypothesized that we could target these pro-inflammatory/cytotoxic lymphocytes by inhibiting co-stimulation through CD137.
  
  
  METHODS
  Isolated PBMC from patients with COPD and healthy controls were stimulated with phytohaemagglutinin (PHA) ± blocking anti-CD137 ± 10(-6) M methylprednislone (MP) (±stimulatory anti-CD137 ± control antibodies). Pro-inflammatory cytokine profiles and expression of granzyme B, by T, NKT-like CD28 ± subsets and NK cells were determined using flow cytometry.
  
  
  RESULTS
  There was a significant decrease in the percentage of T, NKT-like subsets and NK cells producing IFNγ, TNFα and granzyme B in all subjects in the presence of anti-CD137 blocking antibody compared with PHA alone (eg, 60% decrease in CD8 + granzyme B + cells) or MP. Stimulatory anti-CD137 was associated with an increase in the percentage of pro-inflammatory/cytotoxic cells. The inhibitory effect of anti-CD137 on IFNγ, TNFα and granzyme B production by CD28null cells was greater than by CD28+ cells.
  
  
  CONCLUSIONS
  Blocking CD137 expression is associated with downregulation of IFNγ, TNFα and granzyme B by CD8+ T and NKT-like and NK cells. Targeting CD137 may have novel therapeutic implications for patients with COPD.
authors.affiliation: Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia. greg.hodge@health.sa.gov.au.
authors.forename: Greg
authors.initials: G
authors.lastname: Hodge
authors.forename: Mark
authors.initials: M
authors.lastname: Holmes
authors.forename: Hubertus
authors.initials: H
authors.lastname: Jersmann
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: Sandra
authors.initials: S
authors.lastname: Hodge
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D016022:Case-Control Studies; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D058990:Molecular Targeted Therapy; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000188:drug therapy; D012016:Reference Values; D012680:Sensitivity and Specificity; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma