ACUTE INVIVO EFFECTS OF HUMAN RECOMBINANT TUMOR-NECROSIS-FACTOR

Abstract

Tumor necrosis factor is a peptide cytokine that induces hemorrhagic necrosis of some tumors and is responsible for the severe cachexia observed in advanced infectious diseases. We evaluated the acute effects of intravenous administration of purified human recombinant tumor necrosis factor in mice. With as little as 0.01 .mu.g/mouse (0.00045 mg/kg) a peripheral blood lymphopenia and neutrophilia developed as determined by flow cytometric analysis. At 1 .mu.g/mouse, the lymphopenia was both relative (21 .+-. 3% versus 65 .+-. 3%; p < 0.001 treated versus control) and absolute (62 .+-. 10 versus 229 .+-. 29 .times. 104 cells/ml p < 0.001). The neutrophilia was also relative (79 .+-. 3% versus 34 .+-. 3%; p < 0.001 treated versus control) and absolute (237 .+-. 26 versus 110 .+-. 13 .times. 104 cell/ml; p < 0.001). Te neutrophilia was due to an increase in both mature and immature cells. At the higher doses the animals developed hypovolemic shock with an increased hematocrit and watery diarrhea occurred. Microscopic examination of the small bowel disclosed necrosis of the villi. Ultrastructural studies of the small bowel confirmed the necrosis and also showed severe endothelial cell damage, pyknotic nuclei, exocytosis of Paneth cell granules, and extravasation of red blood cells and neutrophils into the interstitium. A vascular leak syndrome developed with preferential fluid loss into the small and large bowel. These data demonstrate the potent in vivo effects of purified human recombinant tumor necrosis factor.