Protective effect of natural TNF-binding protein on human TNF-induced toxicity in mice.
The in vivo protective effect of urinary TNF-binding protein (uTBP) on acute TNF-induced lesions and lethality was assessed in BALB/c mice. Two animal models, the local Shwartzman reaction and galactosamine (GaLN) induced TNF sensitization, were used. In the former, local cutaneous haemorrhagic necrosis induced by 10 micrograms of recombinant human TNF alpha (r-hTNF) was prevented with iv doses of uTPB as low as 1 microgram when administered concomitantly or 10 micrograms when injected intravenously 60 min before or 30 min after the lesion eliciting-dose of r-hTNF. In the latter model, injection of 1 microgram or r-hTNF caused the death of all mice within 36 h. Either 100 or 250 micrograms of uTBP given intravenously simultaneously with r-hTNF/GaLN totally prevented this mortality. In contrast to anti-human TNF monoclonal antibodies, these very same doses of uTBP significantly protected mice even when injected after the lethal r-hTNF dose. These data confirm in relevant in vivo pathological models the TNF inhibiting capacity of the natural soluble TNF receptor I.
Ythier
A
A
Preclinical Pharmacology Department, Ares Serono, Geneva, Switzerland.
Gascon
M P
MP
Juillard
P
P
Vesin
C
C
Wallach
D
D
Grau
G E
GE
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D005260:Female; D005688:Galactosamine / Q000276:immunology; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity
D002352:Carrier Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D005688:Galactosamine