Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin
| Autor: | Scot A. Marsters, Avi Ashkenazi, Steven M. Chamow, Douglas H. Smith, Daniel J. Capon, I S Figari, Diane Pennica, David V. Goeddel, Michael A. Palladino |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Lymphotoxin alpha
Cell Survival medicine.medical_treatment Restriction Mapping Receptors Cell Surface Pharmacology Biology Transfection Receptors Tumor Necrosis Factor Sepsis Mice L Cells Cell surface receptor medicine Animals Humans Cytotoxic T cell Cloning Molecular Receptor Lymphotoxin-alpha Mice Inbred BALB C Salmonella Infections Animal Multidisciplinary Chimera Tumor Necrosis Factor-alpha Septic shock Antibodies Monoclonal hemic and immune systems medicine.disease Shock Septic biological factors Kinetics Cytokine Immunoglobulin G Immunology Dactinomycin Mutagenesis Site-Directed Female Tumor necrosis factor alpha biological phenomena cell phenomena and immunity Chromosome Deletion Immunoglobulin Heavy Chains Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences. 88:10535-10539 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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