Cited by 2,448Sepsis Diagnosis and TreatmentInflammation biomarkers and pathwaysImmune Response and Inflammation

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Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia

Tracey, Kevin J., Fong, Yuman, Hesse, David G., Manogue, Kirk R., Lee, Annette T., Kuo, George C., Lowry, Stephen F., Cerami, Anthony·1987·Nature

DOI 10.1038/330662a0

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Abstract

Bacterial infection of the mammalian bloodstream can lead to overwhelming sepsis, a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure. Cachectin, also known as tumour necrosis factor, is a macrophage-derived peptide hormone released in response to bacterial lipopolysaccharide, and it has been implicated as a principal mediator of endotoxic shock, although its function in bacterial sepsis is not known. Anaesthetized baboons were passively immunized against endogenous cachectin and subsequently infused with an LD100 dose of live Escherichia coli. Control animals (not immunized against cachectin) developed hypotension followed by lethal renal and pulmonary failure. Neutralizing monoclonal anti-cachectin antibody fragments (F(ab')2) administered to baboons only one hour before bacterial challenge protected against shock, but did not prevent critical organ failure. Complete protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion. These results indicate that cachectin is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin offer a potential therapy of life-threatening infection.

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“With the greater knowledge of the etiopathogenesis of sepsis and the critical involvement of tumor necrosis factor-α (TNF-α) and macrophage activation in sepsis progression, a more focused therapeutic approach targeting the immune system has started to grow-up (Tracey et al., 1987).”
Background
Bacteria and Host Interplay in Staphylococcus aureus Septic Arthritis and Sepsis
Jin, T., Mohammad, M., Pullerits, R., & Ali, A. M. (2021) · Pathogens · doi:10.3390/pathogens10020158 · Cited by 81
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Background
Deficiency of the macrophage migration inhibitory factor gene has no significant effect on endotoxaemia
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BackgroundResult
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“It can induce its own synthesis and release by monocytes, cause the clinical manifestations of overwhelming infection, and is a pivotal mediator of lethality from infection (36, 37).”
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“Observations in the pathogenesis of shock have suggested that TNF- is a pivotal cytokine in septic shock (33).”
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Interleukin-10 Prevents Early Cytokine Release in Severe Intraabdominal Infection and Sepsis
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“Tumor necrosis factor (TNF) is a characteristic inflammatory cytokine contributing to cardiovascular collapse in sepsis: recombinant TNF triggers the characteristic symptoms of “septic shock” and TNF neutralization can prevent septic shock in animals when administered before endotoxemia [ 4 ].”
Background
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“TNFa has been also implicated in the mediation of a number of diseases including septic shock syndrome (15), cachexia (16), and AIDS (17, 18) and in the pathogenesis of certain autoimmune diseases (19).”
Background
Pituitary Cytokine and Growth Factor Expression and Action
Ray, D. (1997) · Endocrine Reviews · doi:10.1210/er.18.2.206 · Cited by 69
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Self-citation
Pharmacologic Inhibitors of Tumor Necrosis Factor Production Exert Differential Effects in Lethal Endotoxemia and in Infection with Live Microorganisms in Mice
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“protects against shock after infusion of gram-negative bacteria in primates [4, 5].”
Background
Simultaneous activation of apoptosis and inflammation in pathogenesis of septic shock: a hypothesis1
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G1-4A, an immunomodulatory polysaccharide from Tinospora cordifolia, modulates macrophage responses and protects mice against lipopolysaccharide induced endotoxic shock
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“Passive immunization of endotoxin-sensitive mice with antiserum to TNF substantially reduced the lethal effects of endotoxin (6), and pretreatment of baboons (34) and rabbits (21) with a monoclonal antibody to TNF prevented their deaths after the administration of a 100% lethal dose of live”
MethodSelf-citation
Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice
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“Since antibody to TNF can diminish endotoxin lethality by neutralizing TNF and its actions (7, 55), we tested the effect of passive immunization of endotoxic mice with anti-TNF on PEPCK induction.”
Method
Effect of recombinant tumour necrosis factor on acute infection in mice with Toxoplasma gondii or Trypanosoma cruzi.
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Artesunate Protects Against Sepsis-Induced Lung Injury Via Heme Oxygenase-1 Modulation
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“Moreover, the neutralization of TNF-α or IL-6 improves the survival rate of septic mice [20, 21].”
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Barton, P. A., & Warren, J. S. (1993) · Infection and Immunity · doi:10.1128/iai.61.4.1474-1481.1993 · Cited by 65
“Both experimental and clinical data suggest that TNF is a pivotal endogenous mediator of septic and endotoxic shock (1, 2, 31, 38-40).”
Background
The Tumor Necrosis Factor Family: Family Conventions and Private Idiosyncrasies
Wallach, D. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028431 · Cited by 66
“This has been demonstrated by the therapeutic effects of TNF-blocking agents observed in millions of patients, as well as in experimental animal models for both chronic and acute inflammatory diseases (Tracey et al. 1987; Apostolaki et al. 2010; Sfikakis 2010).”
Background
Oxygen and Surgical Site Infection
Qadan, M., Battista, C. T., Gardner, S. A., Anderson, G., Akça, O., & Polk, H. C. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181e19d1d · Cited by 64
“treatment with antiserum to TNF- was shown to protect mice against endotoxin lethality in vivo.(34,35) The concept did”
Method
Ceramide Kinase Regulates the Production of Tumor Necrosis Factor α (TNFα) via Inhibition of TNFα-converting Enzyme
Lamour, N. F., Wijesinghe, D. S., Mietla, J. A., Ward, K. E., Stahelin, R. V., & Chalfant, C. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.310169 · Cited by 65
Sepsis: State of the art
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Central effects of TNF α on thermogenesis and fever in the rat
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“Although physiological stimulation of BAT has been considered to result almost exclusively from neural release of catecholamines (19) the concentrations (approximately 0.3 10 -7 M) seen in guinea pigs above ( 1 ) may be sufficient to directly stimulate BAT since isolated brown adipocytes are maximally activated by 1…”
BackgroundInfluential
Endogenous mediators in emergency department patients with presumed sepsis: Are levels associated with progression to severe sepsis and death?
Terregino, C. A., Lopez, B. L., Karras, D. J., Killian, A. J., & Arnold, G. K. (2000) · Annals of Emergency Medicine · doi:10.1016/s0196-0644(00)70101-6 · Cited by 64
Animal and human models for sepsis
Schultz, M. J., & van der Poll, T. (2002) · Annals of Medicine · doi:10.1080/078538902321117797 · Cited by 66
“Likewise, other investigators demonstrated that anti-TNF treatment rendered baboons less liable for death after intravenous infusion of bacteria (57).”
Result
Dietary glycine blunts lung inflammatory cell influx following acute endotoxin
Wheeler, M. D., Rose, M., Yamashima, S., Enomoto, N., Seabra, V., Madren, J., & Thurman, R. G. (2000) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2000.279.2.l390 · Cited by 65
Linomide, a novel immunomodulator that prevents death in four models of septic shock
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Background
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Self-citation
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Method
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Background
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BackgroundSelf-citation

Authors: Tracey, K. J., Fong, Y., Hesse, D. G., Manogue, K. R., Lee, A. T., Kuo, G. C., Lowry, S. F., & Cerami, A.
Affiliations: Cornell University (US)
Rockefeller University (US)
ORCID: Tracey, Kevin J.
Fong, Yuman
Kuo, George C.
Cerami, Anthony
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1987-12
Volume: 330
Issue: 6149
Pages: 662-664
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/330662a0
OpenAlex: W2038434279
Cited by: 2,448
References: 1
Citations by year: 2026: 10 · 2025: 13 · 2024: 19 · 2023: 17 · 2022: 13 · 2021: 24 · 2020: 24 · 2019: 32 · 2018: 31 · 2017: 24 · 2016: 40 · 2015: 33 · 2014: 44 · 2013: 43 · 2012: 46
FWCI: 95.90
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: TNF-α, septic shock, bacteremia, Escherichia coli, passive immunization, neutralizing monoclonal antibodies, F(ab')2 fragments, endotoxic shock, organ failure, renal failure, respiratory failure, stress hormones, baboons, sepsis treatment
MeSH terms: Animals, Antibodies, Monoclonal, Blood Pressure, Cardiac Output, Catecholamines, Glucagon, Immunization, Passive, Immunologic Techniques, Leukocyte Count, Papio, Shock, Septic, Tumor Necrosis Factor-alpha, Sepsis

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Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia

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