title: Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study.
abstract: BACKGROUND
  Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) restore immune competence of ex vivo stimulated leukocytes of patients with sepsis, effects on immunoparalysis in vivo are not known.
  
  
  OBJECTIVE
  To investigate the effects of IFN-γ and GM-CSF on immunoparalysis in vivo in humans.
  
  
  METHODS
  We performed a double-blind, placebo-controlled, randomized study in 18 healthy male volunteers that received Escherichia coli endotoxin (LPS; 2 ng/kg, intravenously) on days 1 and 7 (visits 1 and 2). On days 2, 4, and 6, subjects received subcutaneous injections of IFN-γ (100 μg/day; n = 6), GM-CSF (4 μg/kg/day; n = 6), or placebo (NaCl 0.9%; n = 6).
  
  
  RESULTS
  In the placebo group, immunoparalysis was illustrated by a 60% (48-71%) reduction of LPS-induced tumor necrosis factor (TNF)-α plasma concentrations during visit 2 (P = 0.03), whereas the antiinflammatory IL-10 response was not significantly attenuated (39% [2-65%]; P = 0.15). In contrast, in the IFN-γ group, TNF-α concentrations during visit 2 were not significantly attenuated (28% [1-47%]; P = 0.09), whereas the IL-10 response was significantly lower (reduction of 54% [47-66%]; P = 0.03). Compared with the placebo group, the reduction in the LPS-induced TNF-α response during visit 2 was significantly less pronounced in the IFN-γ group (P = 0.01). Moreover, compared with placebo, treatment with IFN-γ increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-γ, but were not statistically significant compared with placebo.
  
  
  CONCLUSIONS
  IFN-γ partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-γ is a promising treatment option to reverse sepsis-induced immunoparalysis.
authors: Radboud University Nijmegen Medical Centre, Department of Intensive Care Medicine, Geert Grooteplein Zuid 10, Nijmegen, The Netherlands. .
authors: Jenneke
authors: J
authors: Leentjens
authors: Matthijs
authors: M
authors: Kox
authors: Rebecca M
authors: RM
authors: Koch
authors: Frank
authors: F
authors: Preijers
authors: Leo A B
authors: LA
authors: Joosten
authors: Johannes G
authors: JG
authors: van der Hoeven
authors: Mihai G
authors: MG
authors: Netea
authors: Peter
authors: P
authors: Pickkers
mesh_terms: D061605:Administration, Intravenous; D004311:Double-Blind Method; D004731:Endotoxins / Q000008:administration & dosage / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016867:Immunocompromised Host; D020382:Interleukin-18 / Q000276:immunology / Q000627:therapeutic use; D008297:Male; D009426:Netherlands; D010865:Pilot Projects; D018805:Sepsis / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D055815:Young Adult
chemical_list: D004731:Endotoxins; D020382:Interleukin-18; D016179:Granulocyte Colony-Stimulating Factor; C044101:endotoxin, Escherichia coli