Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin.

Abstract

Tumor necrosis factors (TNF) alpha and beta are structurally related cytokines that mediate a wide range of immunological, inflammatory, and cytotoxic effects. During bacterial infection of the bloodstream (sepsis), TNF-alpha induction by bacterial endotoxin is thought to be a major factor contributing to the cardiovascular collapse and critical organ failure that can develop. Despite antibiotic therapy, these consequences of sepsis continue to have a high mortality rate in humans. Here we describe a potent TNF antagonist, a TNF receptor (TNFR) immunoadhesin, constructed by gene fusion of the extracellular portion of human type 1 TNFR with the constant domains of human IgG heavy chain (TNFR-IgG). When expressed in transfected human cells, TNFR-IgG is secreted as a disulfide-bonded homodimer. Purified TNFR-IgG binds to both TNF-alpha and TNF-beta and exhibits 6- to 8-fold higher affinity for TNF-alpha than cell surface or soluble TNF receptors. In vitro, TNFR-IgG blocks completely the cytolytic effect of TNF-alpha or TNF-beta on actinomycin D-treated cells and is markedly more efficient than soluble TNFR (24-fold) or monoclonal anti-TNF-alpha antibodies (4-fold) in inhibiting TNF-alpha. In vitro, TNFR-IgG prevents endotoxin-induced lethality in mice when given 0.5 hr prior to endotoxin and provides significant protection when given up to 1 hr after endotoxin challenge. These results confirm the importance of TNF-alpha in the pathogenesis of septic shock and suggest a clinical potential for TNFR-IgG as a preventive and therapeutic treatment in sepsis.

• Authors: A Ashkenazi, S A Marsters, D J Capon, S M Chamow, I S Figari, D Pennica, D V Goeddel, M A Palladino, D H Smith
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 88 Issue 23 Pg. 10535-9 (Dec 01 1991) ISSN: 0027-8424 [Print] United States
• PMID: 1660140 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin G
• Immunoglobulin Heavy Chains
• Lymphotoxin-alpha
• Receptors, Cell Surface
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• Dactinomycin

Topics

• Animals
• Antibodies, Monoclonal
• Cell Survival (drug effects)
• Chimera
• Chromosome Deletion
• Cloning, Molecular
• Dactinomycin (pharmacology)
• Female
• Humans
• Immunoglobulin G (genetics, immunology, isolation & purification)
• Immunoglobulin Heavy Chains (genetics, immunology, isolation & purification)
• Kinetics
• L Cells
• Lymphotoxin-alpha (immunology, metabolism, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mutagenesis, Site-Directed
• Receptors, Cell Surface (genetics, immunology, isolation & purification)
• Receptors, Tumor Necrosis Factor
• Restriction Mapping
• Salmonella Infections, Animal (immunology, prevention & control)
• Shock, Septic (immunology, prevention & control)
• Transfection
• Tumor Necrosis Factor-alpha (immunology, metabolism, pharmacology)