The Journal of Immunology, Vol 156, Issue 6 2221-2230, Copyright © 1996 by American Association of Immunologists

ARTICLES

Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081

KJ Van Zee, LL Moldawer, HS Oldenburg, WA Thompson, SA Stackpole, WJ Montegut, MA Rogy, C Meschter, H Gallati, CD Schiller, WF Richter, H Loetscher, A Ashkenazi, SM Chamow, F Wurm, SE Calvano, SF Lowry and W Lesslauer
Department of Surgery, Cornell University Medical College, New York 10021, USA.

Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5-G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5-G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration.

This article has been cited by other articles:

				J. J. Rosenberg, S. W. Martin, J. E. Seely, O. Kinstler, G. C. Gaines, K. Fukuzuka, J. Rose, T. Kohno, W. J. Boyle, A. Nelson, et al. Development of a novel, nonimmunogenic, soluble human TNF receptor type I (sTNFR-I) construct in the baboon J Appl Physiol, November 1, 2001; 91(5): 2213 - 2223. [Abstract] [Full Text] [PDF]

				M. G. Scott, M. R. Gold, and R. E. W. Hancock Interaction of Cationic Peptides with Lipoteichoic Acid and Gram-Positive Bacteria Infect. Immun., December 1, 1999; 67(12): 6445 - 6453. [Abstract] [Full Text] [PDF]

				W. F. Richter, H. Gallati, and C.-D. Schiller Animal Pharmacokinetics of the Tumor Necrosis Factor Receptor-Immunoglobulin Fusion Protein Lenercept and Their Extrapolation to Humans Drug Metab. Dispos., January 1, 1999; 27(1): 21 - 25. [Abstract] [Full Text]

				S. Smith, S. J. Skerrett, E. Y. Chi, M. Jonas, K. Mohler, and C. B. Wilson The locus of tumor necrosis factor-alpha action in lung inflammation. Am. J. Respir. Cell Mol. Biol., December 1, 1998; 19(6): 881 - 891. [Abstract] [Full Text]

				N. Zantl, A. Uebe, B. Neumann, H. Wagner, J.-R. Siewert, B. Holzmann, C.-D. Heidecke, and K. Pfeffer Essential Role of Gamma Interferon in Survival of Colon Ascendens Stent Peritonitis, a Novel Murine Model of Abdominal Sepsis Infect. Immun., May 1, 1998; 66(5): 2300 - 2309. [Abstract] [Full Text] [PDF]

				C. C. Solorzano, A. Kaibara, P. J. Hess, P. D. Edwards, R. Ksontini, A. Abouhamze, S. McDaniel, J. Frazier, D. Trujillo, G. Kieft, et al. Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon J Appl Physiol, April 1, 1998; 84(4): 1119 - 1130. [Abstract] [Full Text] [PDF]

				A. Haimovitz-Friedman, C. Cordon-Cardo, S. Bayoumy, M. Garzotto, M. McLoughlin, R. Gallily, C. K. Edwards III, E. H. Schuchman, Z. Fuks, and R. Kolesnick Lipopolysaccharide Induces Disseminated Endothelial Apoptosis Requiring Ceramide Generation J. Exp. Med., December 1, 1997; 186(11): 1831 - 1841. [Abstract] [Full Text] [PDF]