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

被引:69
作者
VANZEE, KJ
STACKPOLE, SA
MONTEGUT, WJ
ROGY, MA
CALVANO, SE
HSU, KC
CHAO, M
MESCHTER, CL
LOETSCHER, H
STUBER, D
ETTLIN, U
WIPF, B
LESSLAUER, W
LOWRY, SF
MOLDAWER, LL
机构
[1] CORNELL UNIV,MED CTR,COLL MED,DEPT SURG,NEW YORK,NY 10021
[2] CORNELL UNIV,MED CTR,COLL MED,DEPT CELL BIOL & ANAT,NEW YORK,NY 10021
[3] HOFFMANN LA ROCHE INC,DEPT TOXICOL & PATHOL,NUTLEY,NJ 07110
[4] F HOFFMANN LA ROCHE & CO LTD,DEPT BIOL,CH-4002 BASEL,SWITZERLAND
关键词
D O I
10.1084/jem.179.4.1185
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 TNFalpha (wtTNFalpha) and a novel p55 TNF selective receptor agonist, healthy, anesthetized baboons (Papio sp.) were infused with a near-lethal dose of either wtTNFalpha or a TNFalpha double mutant (dmTNFalpha) that binds specifically to the p55, but not to the.p75, TNF receptor. Both wtTNFalpha and dmTNFalpha produced comparable acute hypotension, tachycardia, increased plasma lactate, and organ dysfunction in Papio. However, administration of wt TNFalpha 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 dmTNFalpha mutant administration. Infusion of dmTNFa resulted in a plasma endogenous TNFalpha 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 TNFalpha. Significant systemic toxicity results from p55 TNF receptor activation, but the role of the p75 TNF receptor in systemic TNF toxicity requires further study.
引用
收藏
页码:1185 / 1191
页数:7
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