RATIONALE: 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. OBJECTIVES: 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). MEASUREMENTS AND MAIN 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.
RCT Entities:
RATIONALE: 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. OBJECTIVES: 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). MEASUREMENTS AND MAIN 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: Willem J M Mulder; Jordi Ochando; Leo A B Joosten; Zahi A Fayad; Mihai G Netea Journal: Nat Rev Drug Discov Date: 2019-07 Impact factor: 84.694
Authors: Timothy R Hercus; Winnie L T Kan; Sophie E Broughton; Denis Tvorogov; Hayley S Ramshaw; Jarrod J Sandow; Tracy L Nero; Urmi Dhagat; Emma J Thompson; Karen S Cheung Tung Shing; Duncan R McKenzie; Nicholas J Wilson; Catherine M Owczarek; Gino Vairo; Andrew D Nash; Vinay Tergaonkar; Timothy Hughes; Paul G Ekert; Michael S Samuel; Claudine S Bonder; Michele A Grimbaldeston; Michael W Parker; Angel F Lopez Journal: Cold Spring Harb Perspect Biol Date: 2018-06-01 Impact factor: 10.005
Authors: Katharine M Irvine; Xuan Banh; Victoria L Gadd; Kyle K Wojcik; Juliana K Ariffin; Sara Jose; Samuel Lukowski; Gregory J Baillie; Matthew J Sweet; Elizabeth E Powell Journal: JCI Insight Date: 2016-06-02
Authors: Shih-Chin Cheng; Brendon P Scicluna; Rob J W Arts; Mark S Gresnigt; Ekta Lachmandas; Evangelos J Giamarellos-Bourboulis; Matthijs Kox; Ganesh R Manjeri; Jori A L Wagenaars; Olaf L Cremer; Jenneke Leentjens; Anne J van der Meer; Frank L van de Veerdonk; Marc J Bonten; Marcus J Schultz; Peter H G M Willems; Peter Pickkers; Leo A B Joosten; Tom van der Poll; Mihai G Netea Journal: Nat Immunol Date: 2016-03-07 Impact factor: 25.606