Combination immunotherapy with soluble tumor necrosis factor receptors plus interleukin 1 receptor antagonist decreases sepsis mortality

Objective: Inhibition of tumor necrosis factor (TNF) or interleukin 1 (IL-1 ) alone has not improved sepsis survival in human clinical trials; therefor e, it has been suggested that blockade of both may be successful. We tested whether combination immunotherapy would improve survival in mice subjected to a lethal lipopolysaccharide (LPS) challenge or the sepsis model of ceca l ligation and puncture. Design: Mice were treated with the combination immunotherapy and challenged with either a lethal dose of lipopolysaccharide or a septic challenge indu ced by cecal ligation and puncture. Setting: University research laboratory. Subjects: Adult, female Balb/c mice. Interventions: Mice were treated with the combination of the IL-l receptor antagonist plus a polyethylene glycol-linked dimer of the TNF soluble recep tor. Measurements and Main Results: LPs lethality was reduced in the treated mic e with a decrease in biologically active TNF in the plasma and peritoneal f luid. In the cecal ligation and puncture (CLP) model of sepsis, this combin ation immunotherapy for 1 day decreased plasma and peritoneal levels of IL- 6 and the murine chemokines KC and MIP-2. However, treatment did not result in a reduction in the hypothermia or peripheral blood alterations that occ ur after CLP, and the 1-day therapy did not result in an improvement in sur vival. In contrast, when combination immunotherapy was extended to 3 days t here was a significant improvement in survival. Conclusions:These data demonstrate that inhibition of both TNF and IL-l wil l decrease the lethality of sepsis initiated by CLP if the combination immu notherapy is provided for a sufficient amount of time.