Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram- negative sepsis

Evans, T. J., Moyes, D., Carpenter, A., Martin, R., Loetscher, H., Lesslauer, W. and Cohen, J. (1994) Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram- negative sepsis. Journal of Experimental Medicine, 180(6), pp. 2173-2179. (PMID:7964492) (PMCID:2191793)

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Abstract

The aim of this study was to compare the ability of both a 55- and 75- kD soluble tumor necrosis factor receptor immunoglobulin G fusion protein (sTNFR-IgG) in protecting against death in a murine model of gram-negative sepsis. Pretreatment with 250 micrograms of the p75 construct delayed but did not avert death in this model, reducing peak bioactive TNF-alpha levels after infection from 76.4 ng ml-1 in control mice to 4.7 ng ml-1 in the treated group (p < 0.05, two-sample t test). However, these low levels of bioactive TNF-alpha persisted in the p75 fusion protein-treated animals compared with the controls and were sufficient to mediate delayed death. In contrast, pretreatment with 200 micrograms of the p55 sTNFR-IgG gave excellent protection against death with complete neutralization of circulating TNF. Studies of the binding of TNF-alpha with the soluble TNFR fusion proteins showed that the p75 fusion construct exchanges bound TNF-alpha about 50-100-fold faster than the p55 fusion protein. Thus, although both fusion proteins in equilibrium bind TNF-alpha with high affinity, the TNF-alpha p55 fusion protein complex is kinetically more stable than the p75 fusion construct, which thus acts as a TNF carrier. The persistent release of TNF-alpha from the p75 fusion construct limits its therapeutic effect in this model of sepsis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Evans, Professor Tom
Authors: Evans, T. J., Moyes, D., Carpenter, A., Martin, R., Loetscher, H., Lesslauer, W., and Cohen, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Experimental Medicine
Publisher:Rockefeller University Press
ISSN:0022-1007
ISSN (Online):1540-9538

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