title: Targeting peripheral blood pro-inflammatory CD28null T cells and natural killer T-like cells by inhibiting CD137 expression: possible relevance to treatment of bronchiolitis obliterans syndrome.
abstract: BACKGROUND
  We have shown that bronchiolitis obliterans syndrome (BOS) is associated with attenuated suppression of pro-inflammatory cytokines and granzyme B by steroid-resistant peripheral blood CD28nullCD137+ T cells and natural killer T (NKT)-like cells. We hypothesized that we could target these steroid-resistant lymphocytes by inhibiting costimulation through CD137.
  
  
  METHODS
  Isolated peripheral blood mononuclear cells from transplant patients with stable lung function, patients with BOS, and healthy controls were stimulated with anti-CD3 with and without blocking anti-CD137 and with and without 10(-6) mol/liter methylprednisolone (MP) (with and without stimulatory anti-CD137). Pro-inflammatory cytokine profiles and expression of the cytotoxic mediator, granzyme B, by CD28null T and NKT-like cells were determined using flow cytometry.
  
  
  RESULTS
  There was a significant decrease in the percentage of CD28null T and NKT-like cells producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and granzyme B in all individuals in the presence of anti-CD137 blocking antibody compared with anti-CD3 alone (eg, 30% decrease in CD8+CD28null TNF-α+ cells). Stimulatory anti-CD137 was associated with an increase in pro-inflammatory/cytotoxic cells. Treatment with anti-CD137 blocking with prednisolone further reduced IFN-γ, TNF-α, and granzyme B in these cells.
  
  
  CONCLUSIONS
  Blocking CD137 expression in CD28null T cells and NKT-like cells is associated with down-regulation of IFN-γ, TNF-α, and granzyme B. Targeting CD137 reduces pro-inflammatory/cytotoxic expression in steroid-resistant CD28null T and NKT-like cells and may have therapeutic implications for patients with BOS.
authors.affiliation: Lung Research, Hanson Institute, Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; South Australian Lung Transplant Service, University of Adelaide, Adelaide, South Australia, Australia. Electronic address: greg.hodge@health.sa.gov.au.
authors.forename: Greg
authors.initials: G
authors.lastname: Hodge
authors.forename: Sandra
authors.initials: S
authors.lastname: Hodge
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: Mark
authors.initials: M
authors.lastname: Holmes
mesh_terms: D000328:Adult; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000378:metabolism; D018106:CD28 Antigens / Q000172:deficiency* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation; D008775:Methylprednisolone / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D011183:Postoperative Complications / Q000188:drug therapy / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D053804:Granzymes; D008775:Methylprednisolone
keywords: BOS; CD28null T cells; IFN-γ; TNF-α; blocking CD137; lung transplant