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The Journal of Immunology, Vol 151, Issue 3 1548-1561, Copyright © 1993 by American Association of Immunologists

ARTICLES

Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists

KM Mohler, DS Torrance, CA Smith, RG Goodwin, KE Stremler, VP Fung, H Madani and MB Widmer
Department of Immunology, Immunex Corporation, Seattle, WA 98101.

Two forms (monomeric or dimeric) of the extracellular, ligand-binding portion of the human p80 cell-surface receptor for TNF were used to antagonize TNF activity in vitro and in vivo. The dimeric sTNFR:Fc molecule was a more potent inhibitor of TNF than the monomeric sTNFR (50 to 1000x), as assessed in vitro by inhibition of TNF binding or bioactivity and in vivo by protection of mice from an otherwise lethal injection of LPS. Surprisingly, the dimeric sTNFR:Fc construct demonstrated a beneficial effect even when administered 3 h after a lethal LPS injection (i.e., after serum TNF levels had peaked and receded). To study the mechanism by which the soluble TNFR functions in vivo, serum TNF levels were examined in mice given LPS in the presence or absence of soluble receptor. Administration of a mortality-reducing dose of sTNFR:Fc ablated the rise in serum TNF bioactivity that normally occurs in response to LPS. However, TNF bioactivity was revealed in these "TNF-negative" serum samples when the L929 bioassay was modified by inclusion of a mAb that blocks the binding of murine TNF to the human soluble TNFReceptor. These results indicate that the absence of direct cytolytic activity in the L929 assay was caused by neutralization of TNF, rather than to an absence of TNF in the serum. Moreover, administration of either monomeric sTNFR or low doses of dimeric sTNFR:Fc actually resulted in increased serum TNF levels compared to mice given LPS but no soluble receptor. However, these "agonistic" doses of soluble receptor did not lead to increased mortality when an LD60 dose of LPS was given. Thus, dimeric sTNFR are effective inhibitors of TNF and under some circumstances function simultaneously as both TNF "carriers" and antagonists of TNF biologic activity.


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 ThoraxHome page
L. Armstrong, N. M Foley, and A. B Millar
Inter-relationship between tumour necrosis factor-alpha (TNF-alpha ) and TNF soluble receptors in pulmonary sarcoidosis
Thorax, June 1, 1999; 54(6): 524 - 530.
[Abstract] [Full Text]

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 J. Immunol.Home page
W. E. Carson, H. Yu, J. Dierksheide, K. Pfeffer, P. Bouchard, R. Clark, J. Durbin, A. S. Baldwin, J. Peschon, P. R. Johnson, et al.
A Fatal Cytokine-Induced Systemic Inflammatory Response Reveals a Critical Role for NK Cells
J. Immunol., April 15, 1999; 162(8): 4943 - 4951.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
R.-Y. Pan, X. Xiao, S.-L. Chen, J. Li, L.-C. Lin, H.-J. Wang, and Y.-P. Tsao
Disease-Inducible Transgene Expression from a Recombinant Adeno-Associated Virus Vector in a Rat Arthritis Model
J. Virol., April 1, 1999; 73(4): 3410 - 3417.
[Abstract] [Full Text]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. van der Poll, E. Endert, S. M. Coyle, J. M. Agosti, and S. F. Lowry
Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 1999; 276(2): R357 - R362.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
I. Spyridopoulos, N. Principe, K. L. Krasinski, S.-h. Xu, M. Kearney, M. Magner, J. M. Isner, and D. W. Losordo
Restoration of E2F Expression Rescues Vascular Endothelial Cells From Tumor Necrosis Factor-{alpha}–Induced Apoptosis
Circulation, December 22, 1998; 98(25): 2883 - 2890.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
K. L. Davenpeck, J. Zagorski, R. P. Schleimer, and B. S. Bochner
Lipopolysaccharide-Induced Leukocyte Rolling and Adhesion in the Rat Mesenteric Microcirculation: Regulation by Glucocorticoids and Role of Cytokines
J. Immunol., December 15, 1998; 161(12): 6861 - 6870.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
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]

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 J. Immunol.Home page
C. L. Chirinos-Rojas, M. W. Steward, and C. D. Partidos
A Peptidomimetic Antagonist of TNF-{alpha}-Mediated Cytotoxicity Identified from a Phage-Displayed Random Peptide Library
J. Immunol., November 15, 1998; 161(10): 5621 - 5626.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. Zaina, R. V. S. Newton, M. R. Paul, and C. F. Graham
Local Reduction of Organ Size in Transgenic Mice Expressing a Soluble Insulin-Like Growth Factor II/Mannose-6-Phosphate Receptor
Endocrinology, September 1, 1998; 139(9): 3886 - 3895.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
X. Meng, L. Ao, D. R. Meldrum, B. S. Cain, B. D. Shames, C. H. Selzman, A. Banerjee, and A. H. Harken
TNF-alpha and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 1998; 275(2): R502 - R508.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
B. Bozkurt, S. B. Kribbs, F. J. Clubb Jr, L. H. Michael, V. V. Didenko, P. J. Hornsby, Y. Seta, H. Oral, F. G. Spinale, and D. L. Mann
Pathophysiologically Relevant Concentrations of Tumor Necrosis Factor-{alpha} Promote Progressive Left Ventricular Dysfunction and Remodeling in Rats
Circulation, April 14, 1998; 97(14): 1382 - 1391.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
D. R. Meldrum
Tumor necrosis factor in the heart
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1998; 274(3): R577 - R595.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
J. J. Peschon, D. S. Torrance, K. L. Stocking, M. B. Glaccum, C. Otten, C. R. Willis, K. Charrier, P. J. Morrissey, C. B. Ware, and K. M. Mohler
TNF Receptor-Deficient Mice Reveal Divergent Roles for p55 and p75 in Several Models of Inflammation
J. Immunol., January 15, 1998; 160(2): 943 - 952.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. V. Turnbull and C. L. Rivier
Intracerebroventricular Passive Immunization. I. The Effect of Intracerebroventricular Administration of an Antiserum to Tumor Necrosis Factor-{alpha} on the Plasma Adrenocorticotropin Response to Lipopolysaccharide in Rats
Endocrinology, January 1, 1998; 139(1): 119 - 127.
[Abstract] [Full Text] [PDF]

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 BloodHome page
T. Yen, C. A. Harrison, J. M. Devery, S. Leong, S. E. Iismaa, T. Yoshimura, and C. L. Geczy
Induction of the S100 Chemotactic Protein, CP-10, in Murine Microvascular Endothelial Cells by Proinflammatory Stimuli
Blood, December 15, 1997; 90(12): 4812 - 4821.
[Abstract] [Full Text] [PDF]

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 BloodHome page
H. L. Dickensheets, S. L. Freeman, M. F. Smith Jr, and R. P. Donnelly
Interleukin-10 Upregulates Tumor Necrosis Factor Receptor Type-II (p75) Gene Expression in Endotoxin-Stimulated Human Monocytes
Blood, November 15, 1997; 90(10): 4162 - 4171.
[Abstract] [Full Text] [PDF]

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 JEMHome page
J. Ruby, H. Bluethmann, and J. J. Peschon
Antiviral Activity of Tumor Necrosis Factor (TNF) Is Mediated via p55 and p75 TNF Receptors
J. Exp. Med., November 3, 1997; 186(9): 1591 - 1596.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
R. M. VISCARDI, J. D. HASDAY, K. F. GUMPPER, V. TACIAK, A. B. CAMPBELL, and T. W. PALMER
Cromolyn Sodium Prophylaxis Inhibits Pulmonary Proinflammatory Cytokines in Infants at High Risk for Bronchopulmonary Dysplasia
Am. J. Respir. Crit. Care Med., November 1, 1997; 156(5): 1523 - 1529.
[Abstract] [Full Text]

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 JEMHome page
M. A. Degli-Esposti, P. J. Smolak, H. Walczak, J. Waugh, C.-P. Huang, R. F. DuBose, R. G. Goodwin, and C. A. Smith
Cloning and Characterization of TRAIL-R3, a Novel Member of the Emerging TRAIL Receptor Family
J. Exp. Med., October 6, 1997; 186(7): 1165 - 1170.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
E. PRESTERL, T. STAUDINGER, M. PETTERMANN, A. LASSNIGG, H. BURGMANN, S. WINKLER, M. FRASS, and W. GRANINGER
Cytokine Profile and Correlation to the APACHE III and MPM II Scores in Patients with Sepsis
Am. J. Respir. Crit. Care Med., September 1, 1997; 156(3): 825 - 832.
[Abstract] [Full Text] [PDF]

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 BloodHome page
A. Kiani, A. Tschiersch, E. Gaboriau, F. Otto, A. Seiz, H.-P. Knopf, P. Stutz, L. Farber, U. Haus, C. Galanos, et al.
Downregulation of the Proinflammatory Cytokine Response to Endotoxin by Pretreatment With the Nontoxic Lipid A Analog SDZ MRL 953 in Cancer Patients
Blood, August 15, 1997; 90(4): 1673 - 1683.
[Abstract] [Full Text] [PDF]

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 Innate ImmunityHome page
A.J. Camerota, L. Logdberg, P. Lake, V.A. Larkin, and M.P. Fink
Delayed therapy with a polymyxin B-dextran conjugate (PMX-622) improves survival in rabbits with Gram-negative peritonitis
Innate Immunity, August 1, 1997; 4(4): 285 - 292.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
L. Williams-Abbott, B. N. Walter, T. C. Cheung, C. R. Goh, A. G. Porter, and C. F. Ware
The Lymphotoxin-alpha (LTalpha ) Subunit Is Essential for the Assembly, but Not for the Receptor Specificity, of the Membrane-anchored LTalpha 1beta 2 Heterotrimeric Ligand
J. Biol. Chem., August 1, 1997; 272(31): 19451 - 19456.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
L. W. Moreland, S. W. Baumgartner, M. H. Schiff, E. A. Tindall, R. M. Fleischmann, A. L. Weaver, R. E. Ettlinger, S. Cohen, W. J. Koopman, K. Mohler, et al.
Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)-Fc Fusion Protein
N. Engl. J. Med., July 17, 1997; 337(3): 141 - 147.
[Abstract] [Full Text] [PDF]

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 StrokeHome page
F. C. Barone, B. Arvin, R. F. White, A. Miller, C. L. Webb, R. N. Willette, P. G. Lysko, and G. Z. Feuerstein
Tumor Necrosis Factor-{alpha} : A Mediator of Focal Ischemic Brain Injury
Stroke, June 1, 1997; 28(6): 1233 - 1244.
[Abstract] [Full Text]

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 BloodHome page
T. van der Poll, S. M. Coyle, M. Levi, P. M. Jansen, M. Dentener, K. Barbosa, W. A. Buurman, C. E. Hack, J. W. ten Cate, J. M. Agosti, et al.
Effect of a Recombinant Dimeric Tumor Necrosis Factor Receptor on Inflammatory Responses to Intravenous Endotoxin in Normal Humans
Blood, May 15, 1997; 89(10): 3727 - 3734.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
A. V. Turnbull, F. J. Pitossi, J.-J. Lebrun, S. Lee, J. C. Meltzer, D. M. Nance, A. del Rey, H. O. Besedovsky, and C. Rivier
Inhibition of Tumor Necrosis Factor-alpha Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats
J. Neurosci., May 1, 1997; 17(9): 3262 - 3273.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Al-Shamkhani, S. Mallett, M. H. Brown, W. James, and A. N. Barclay
Affinity and Kinetics of the Interaction between Soluble Trimeric OX40 Ligand, a Member of the Tumor Necrosis Factor Superfamily, and Its Receptor OX40 on Activated T Cells
J. Biol. Chem., February 21, 1997; 272(8): 5275 - 5282.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. E. Ross and M. A. Caligiuri
Cytokine-Induced Apoptosis of Human Natural Killer Cells Identifies a Novel Mechanism to Regulate the Innate Immune Response
Blood, February 1, 1997; 89(3): 910 - 918.
[Abstract] [Full Text] [PDF]

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 Reproductive SciencesHome page
P. L. Fidel Jr, R. Romero, J. Cutright, N. Wolf, R. Gomez, H. Araneda, M. Ramirez, and B. H. Yoon
Treatment With the Interleukin-1 Receptor Antagonist and Soluble Tumor Necrosis Factor Receptor Fc Fusion Protein Does Not Prevent Endotoxin-Induced Preterm Parturition in Mice
Reproductive Sciences, January 1, 1997; 4(1): 22 - 26.
[Abstract] [PDF]

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 NEJMHome page
M. S. Whiteley, M.-P. Glauser, J. Cohen, C. J. Fisher, J. M. Agosti, and S. M. Opal
Tumor Necrosis Factor Receptor:Fc Fusion Protein in Septic Shock
N. Engl. J. Med., November 21, 1996; 335(21): 1607 - 1609.
[Full Text]

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 Stem CellsHome page
M. Freedman, J. Hitzler, N Bunin, T Grunberger, and J Squire
Juvenile chronic myelogenous leukemia multilineage CD34+ cells: aberrant growth and differentiation properties
Stem Cells, November 1, 1996; 14(6): 690 - 701.
[Abstract]

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 Arch SurgHome page
R. D. Acton, P. S. Dahlberg, M. E. Uknis, H. G. Klaerner, G. S. Fink, J. G. Norman, and D. L. Dunn
Differential Sensitivity to Escherichia coli Infection in Mice Lacking Tumor Necrosis Factor p55 or Interleukin-1 p80 Receptors
Arch Surg, November 1, 1996; 131(11): 1216 - 1221.
[Abstract] [PDF]

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 NEJMHome page
C. J. Fisher, J. M. Agosti, S. M. Opal, S. F. Lowry, R. A. Balk, J. C. Sadoff, E. Abraham, R. M.H. Schein, E. Benjamin, and The Soluble TNF Receptor Sepsis Study Group
Treatment of Septic Shock with the Tumor Necrosis Factor Receptor:Fc Fusion Protein
N. Engl. J. Med., June 27, 1996; 334(26): 1697 - 1702.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
M. Packer
Is Tumor Necrosis Factor an Important Neurohormonal Mechanism in Chronic Heart Failure?
Circulation, September 15, 1995; 92(6): 1379 - 1382.
[Full Text]

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 CirculationHome page
R. Ferrari, T. Bachetti, R. Confortini, C. Opasich, O. Febo, A. Corti, G. Cassani, and O. Visioli
Tumor Necrosis Factor Soluble Receptors in Patients With Various Degrees of Congestive Heart Failure
Circulation, September 15, 1995; 92(6): 1479 - 1486.
[Abstract] [Full Text]


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