A HUMAN TUMOR-NECROSIS-FACTOR (TNF) ALPHA-MUTANT THAT BINDS EXCLUSIVELY TO THE P55 TNF RECEPTOR PRODUCES TOXICITY IN THE BABOON

A number of recent studies have demonstrated that cellular responses t o tumor necrosis factor (TNF) mediated by the p55 and the p75 TNF rece ptors are distinct. To evaluate the relative in vivo toxicities of wil d-type TNFalpha (wtTNFalpha) and a novel p55 TNF selective receptor ag onist, healthy, anesthetized baboons (Papio sp.) were infused with a n ear-lethal dose of either wtTNFalpha or a TNFalpha double mutant (dmTN Falpha) that binds specifically to the p55, but not to the.p75, TNF re ceptor. Both wtTNFalpha and dmTNFalpha produced comparable acute hypot ension, tachycardia, increased plasma lactate, and organ dysfunction i n Papio. However, administration of wt TNFalpha produced a marked gran ulocytosis and loss of granulocyte TNF receptors, whereas little if an y changes in neutrophil number or cell surface TNF receptor density we re seen after dmTNFalpha mutant administration. Infusion of dmTNFa res ulted in a plasma endogenous TNFalpha response that peaked after 90-12 0 min. We conclude that selective p55 TNF receptor activation is assoc iated with early hemodynamic changes and the autocrine release of endo genous TNFalpha. Significant systemic toxicity results from p55 TNF re ceptor activation, but the role of the p75 TNF receptor in systemic TN F toxicity requires further study.