Prevention and treatment of endotoxin and sepsis lethality with recombinant human tumor necrosis factor

Tumor necrosis factor (TNF) is a macrophage product released in response to endotoxin that has been implicated as a cause of the toxicity and lethality seen in septic shock. Previous work suggests that tolerance to nutritional and lethal effects of TNF occur after repeated exposure to recombinant tumor necrosis factor (rTNF). In this study pretreatment of rats with a single low intravenous dose of rTNF prevented subsequent death when a lethal dose of rTNF was administered 24 hours later (tolerance or tachyphylaxis). Pretreatment with rTNF also afforded protection against the lethal effects of either endotoxin or cecal ligation and puncture when rats were challenged 24 hours later. Recombinant TNF injected 6 hours after cecal ligation and puncture initially resulted in a significant survival advantage for treated animals. When this experiment was repeated with a different lot of rTNF, however, the therapeutic benefit of rTNF was not obtained until the dose was decreased by a factor of 10. Protection against the lethal effects of cecal ligation and puncture did not occur when rTNF was given 24 hours after the insult. A single low dose of rTNF can result in tolerance or tachyphylaxis to the lethal effects of TNF. The results suggest that the early administration of low-dose rTNF may be useful in the prevention and treatment of the lethality of sepsis.