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

• Published in: Critical care medicine Vol. 29; no. 3; p. 473
• Main Authors: Remick, D G, Call, D R, Ebong, S J, Newcomb, D E, Nybom, P, Nemzek, J A, Bolgos, G E
• Format: Journal Article
• Language: English
• Published: United States 01.03.2001
• Subjects: Animals; Antigens, CD - immunology; Antigens, CD - therapeutic use; Ascitic Fluid - chemistry; Cecum - surgery; Chemokine CXCL2; Chemokines - analysis; Chemokines - blood; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections - immunology; Escherichia coli Infections - metabolism; Escherichia coli Infections - microbiology; Escherichia coli Infections - mortality; Escherichia coli Infections - therapy; Female; Immunotherapy - methods; Interleukin 1 Receptor Antagonist Protein; Interleukin-6 - analysis; Interleukin-6 - blood; Ligation; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Plasma - chemistry; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - therapeutic use; Receptors, Tumor Necrosis Factor, Type I; Sepsis - immunology; Sepsis - metabolism; Sepsis - microbiology; Sepsis - mortality; Sepsis - therapy; Sialoglycoproteins - immunology; Sialoglycoproteins - therapeutic use; Survival Analysis; Time Factors; Tumor Necrosis Factor-alpha - analysis; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0090-3493
• DOI: 10.1097/00003246-200103000-00001

Inhibition of tumor necrosis factor (TNF) or interleukin 1 (IL-1) alone has not improved sepsis survival in human clinical trials; therefore, 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 cecal ligation and puncture. Mice were treated with the combination immunotherapy and challenged with either a lethal dose of lipopolysaccharide or a septic challenge induced by cecal ligation and puncture. University research laboratory. Adult, female Balb/c mice. Mice were treated with the combination of the IL-1 receptor antagonist plus a polyethylene glycol-linked dimer of the TNF soluble receptor. LPS lethality was reduced in the treated mice with a decrease in biologically active TNF in the plasma and peritoneal fluid. In the cecal ligation and puncture (CLP) model of sepsis, this combination 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 occur after CLP, and the 1-day therapy did not result in an improvement in survival. In contrast, when combination immunotherapy was extended to 3 days there was a significant improvement in survival. These data demonstrate that inhibition of both TNF and IL-1 will decrease the lethality of sepsis initiated by CLP if the combination immunotherapy is provided for a sufficient amount of time.