Abstract
The pleiotropic cytokine tumour necrosis factor-alpha (TNF) is thought to play a central role in infectious, inflammatory and autoimmune diseases. Critical to the understanding and management of TNF-associated pathology is the development of highly specific agents capable of modifying TNF activity. We evaluated the ability of a high affinity mouse/human chimeric anti-TNF monoclonal antibody (cA2) to neutralize the in vitro and in vivo biological effects of TNF. cA2 inhibited TNF-induced mitogenesis and IL-6 secretion by human fibroblasts, TNF-priming of human neutrophils, and the stimulation of human umbilical vein endothelial cells by TNF as measured by the expression of E-selectin, ICAM-1 and procoagulant activity. cA2 also specifically blocked TNF-induced adherence of human neutrophils to an endothelial cell monolayer. Receptor binding studies suggested that neutralization resulted from cA2 blocking of TNF binding to both p55 and p75 TNF receptors on the cells. In vivo, repeated administration of cA2 to transgenic mice that constitutively express human TNF reversed the cachectic phenotype and prevented subsequent mortality. These results demonstrated that cA2 effectively neutralized a broad range of TNF biological activities both in vitro and in vivo.
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology*
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Blood Coagulation Factors / biosynthesis
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Blood Coagulation Factors / genetics
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Cachexia / physiopathology
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Cachexia / prevention & control*
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Cell Adhesion / drug effects
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Cell Adhesion Molecules / biosynthesis
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Cell Adhesion Molecules / genetics
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Cell Division / drug effects
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Cells, Cultured
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E-Selectin
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Infliximab
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Interleukin-6 / metabolism
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Mice
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Mice, Transgenic
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Neutralization Tests
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Neutrophils / drug effects
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Recombinant Fusion Proteins / immunology*
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Recombinant Proteins / pharmacology
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Respiratory Burst / drug effects
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Thromboplastin*
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / immunology*
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Tumor Necrosis Factor-alpha / toxicity
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Umbilical Veins
Substances
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Antibodies, Monoclonal
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Blood Coagulation Factors
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Cell Adhesion Molecules
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E-Selectin
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Interleukin-6
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Recombinant Fusion Proteins
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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endothelial cell procoagulant activity
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Intercellular Adhesion Molecule-1
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Thromboplastin
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Infliximab