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

Rationale: Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-gamma 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-gamma 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-gamma (100 mu g/day; n = 6), GM-CSF (4 mu g/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)-alpha 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-gamma group, TNF-alpha 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-alpha response during visit 2 was significantly less pronounced in the IFN-gamma group (P = 0.01). Moreover, compared with placebo, treatment with IFN-gamma increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-gamma, but were not statistically significant compared with placebo. Conclusions: IFN-gamma partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-gamma is a promising treatment option to reverse sepsis-induced immunoparalysis.