Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science, 1985, 229(4716):869-871. Classical article.

Laboratory of Medical Biochemistry, Rockefeller University, New York, NY 10021, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(1):7-9.
Source: PubMed


A highly specific polyclonal rabbit antiserum directed against murine cachectinltumor necrosis factor (TNF) was prepared. When BALBIc mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin. Antiserum to cachectin/TNF did not mitigate the febrile response of endotoxin-treated animals, and very high doses of endotoxin could overcome the protective effect. The median lethal dose of endotoxin in mice pretreated with 50 microliters of the specific antiserum was approximately 2.5 times greater the median lethal dose for controls given nonimmune serum. The data suggest that cachectinlTNF is one of the principal mediators of the lethal effect of endotoxin.

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    • "But as predicted in the wider literature (above), it generated side effects that mimicked the onset of severe sepsis [48]. Yet while prior anti-TNF antibody prevented the illness caused by injecting LPS to induce experimental sepsis, it was of no help when administered to mice that had already been made sick by LPS [39]. This gave fair warning that such antibody was likely to be impractical for treating acute inflammatory disease once it is underway, and so it proved when etanercept, a major commercial anti-TNF biological agent, was first tested in sepsis patients [49]. "
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    ABSTRACT: Tumor necrosis factor (TNF) is an ancient and widespread cytokine required in small amounts for much physiological function. Higher concentrations are central to innate immunity, but if unchecked this cytokine orchestrates much chronic and acute disease, both infectious and noninfectious. While being a major proinflammatory cytokine, it also controls homeostasis and plasticity in physiological circumstances. For the last decade or so these principles have been shown to apply to the central nervous system as well as the rest of the body. Nevertheless, whereas this approach has been a major success in treating noncerebral disease, its investigation and potential widespread adoption in chronic neurological conditions has inexplicably stalled since the first open trial almost a decade ago. While neuroscience is closely involved with this approach, clinical neurology appears to be reticent in engaging with what it offers patients. Unfortunately, the basic biology of TNF and its relevance to disease is largely outside the traditions of neurology. The purpose of this review is to facilitate lowering communication barriers between the traditional anatomically based medical specialties through recognition of shared disease mechanisms and thus advance the prospects of a large group of patients with neurodegenerative conditions for whom at present little can be done.
    Full-text · Article · Jul 2015 · Neural Plasticity
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    • "The first group is the early proinflammatory mediators, such as TNF-α and IL-1β, which are induced within hours after the induction of sepsis. Initial experimental observations have suggested that the inhibition of these cytokines with neutralizing antibodies is beneficial in the treatment of sepsis [31]. However, clinical trials and more elegant animal studies have shown that the neutralization of early cytokines does not protect against sepsis [32]. "
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    ABSTRACT: The nuclear DNA binding protein high mobility group box 1 (HMGB1) has recently been suggested to act as a late mediator of septic shock. The effect of ((S)-6,7-dihydroxy-1-(4-hydroxynaphthylmethyl)-1,2,3,4-tetrahydroisoquinoline alkaloid, also known as THI-56, in an experimental model of sepsis was investigated. THI-56 exhibited potent anti-inflammatory properties in response to LPS in RAW 264.7 cells. In particular, THI-56 significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the release of HMGB1 in activated macrophages. THI-56 activated NE-F2-regulated factor 2 (Nrf-2)/heme oxygenase 1 (HO-1). The specific knockdown of the HO-1 gene by HO-1 siRNA significantly reversed the inhibitory effects of THI-56 on iNOS expression and HMGB1 release in LPS-stimulated macrophages. Importantly, THI-56 administration protected animals from death induced by either a lethal dose of LPS or cecal ligation and puncture (CLP). Furthermore, the ALT, AST, BUN, creatinine, and HMGB1 levels in the blood were significantly increased in CLP-induced septic mice, and the administration of THI-56 reduced these levels in a concentration-dependent and zinc protoporphyrin IX (ZnPPIX)-sensitive manner. In addition, the administration of THI-56 significantly ameliorated not only lung damage but also macrophage infiltration in the livers of CLP-induced septic mice, and these effects were also abrogated in the presence of ZnPPIX. Thus, we conclude that THI-56 significantly attenuates the proinflammatory response induced by LPS and reduces organ damage in a CLP-induced sepsis model through the upregulation of Nrf-2/HO-1.
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