A Human Tumor Necrosis Factor (TNF) c~ Mutant That Binds Exclusively to the p55 TNF Receptor Produces Toxicity in the Baboon By Kimberly

A number of recent studies have demonstrated that cellular responses to tumor necrosis factor (TNF) mediated by the p55 and the p75 TNF receptors are distinct. To evaluate the relative in vivo toxicities of wild-type TNFot (wtTNFc~) and a novel p55 TNF selective receptor agonist, healthy, anesthetized baboons (Papio sF) were infused with a near-lethal dose of either wtTNFc~ or a TNFc~ double mutant (dmTNFo 0 that binds specifically to the p55, but not to the p75, TNF receptor. Both wtTNFc~ and dmTNFcr produced comparable acute hypotension, tachycardia, increased plasma lactate, and organ dysfunction in Papio. However, administration of wt TNFo~ produced a marked granulocytosis and loss of granulocyte TNF receptors, whereas little if any changes in neutrophil number or cell surface TNF receptor density were seen after dmTNFcx mutant administration. Infusion of dmTNFcx resulted in a plasma endogenous TNFc~ response that peaked after 90-120 min. We conclude that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNFc~. Significant systemic toxicity results from p55 TNF receptor activation, but the role of the p75 TNF receptor in systemic TNF toxicity requires further study.