Reversal of Immunoparalysis in Humans In Vivo A Double-Blind, Placebo-controlled, Randomized Pilot Study

• Published in: American journal of respiratory and critical care medicine Vol. 186; no. 9; pp. 838 - 845
• Main Authors: Leentjens, Jenneke, Kox, Matthijs, Koch, Rebecca M., Preijers, Frank, Joosten, Leo A. B., van der Hoeven, Johannes G., Netea, Mihai G., Pickkers, Peter
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.11.2012
• Subjects: Administration, Intravenous; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Cytokines; Double-Blind Method; Emergency and intensive care: metabolism and nutrition disorders. Enteral and parenteral nutrition; Endotoxins - administration & dosage; Endotoxins - immunology; Experiments; Granulocyte Colony-Stimulating Factor - immunology; Granulocyte Colony-Stimulating Factor - therapeutic use; Granulocytes; Humans; Immune Tolerance - drug effects; Immune Tolerance - immunology; Immunocompromised Host; Infections; Intensive care medicine; Interleukin-18 - immunology; Interleukin-18 - therapeutic use; Leukocytes; Lymphocytes; Male; Medical sciences; Netherlands; Pilot Projects; Sepsis; Sepsis - complications; Sepsis - drug therapy; Sepsis - immunology; Tumor necrosis factor-TNF; Young Adult; Netherlands; Human; Infection; Sepsis syndrome; granulocyte-macrophage colony―stimulating factor; Intensive care; IFN-γ; Lipopolysaccharide; immunoparalysis; Granulocyte macrophage colony stimulating factor; Resuscitation; sepsis
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201204-0645OC

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. To investigate the effects of IFN-γ and GM-CSF on immunoparalysis in vivo in humans. 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). 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. 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.