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.
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.
Department of Infectious Diseases and Bacteriology, Royal Postgraduate Medical School, London, UK.
T J
TJ
Evans
D
D
Moyes
A
A
Carpenter
R
R
Martin
H
H
Loetscher
W
W
Lesslauer
J
J
Cohen
D000818:Animals; D004927:Escherichia coli Infections / Q000097:blood / Q000276:immunology / Q000628:therapy*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D009500:Neutralization Tests; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D018805:Sepsis / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha