Treatment of Septic Shock with the Tumor Necrosis Factor Receptor:Fc Fusion Protein

Fisher, Charles J.; Agosti, Jan M.; Opal, Steven M.; Lowry, Stephen F.; Balk, R.A.; Sadoff, Jerald C.; Abraham, Edward; Schein, Roland M. H.; Benjamin, Ernest

doi:10.1056/nejm199606273342603

Cited by 1,120 publications

(544 citation statements)

References 46 publications

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“…As a result, blocking TNF-␣ is protective in mouse models of TSS with D-galN sensitization. Administration of anti-TNF-␣ has not been protective in bacterial shock including that caused by S. aureus in humans 38 and in mouse models of S. aureus sepsis, 63 possibly because other cytokines also have an important role. For example, it was observed that the systemic levels of the relatively new cytokine IL-17 was profoundly elevated in HLA-DR3 transgenic mice with SAg-induced TSS.…”

Section: Discussionmentioning

confidence: 99%

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Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Tilahun

Marietta

et al. 2011

The American Journal of Pathology

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Among the exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgs in vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such as D-galactosamine (D-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS without D-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4 ؉ and CD8؉), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in the D-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with

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Section: Discussionmentioning

confidence: 99%

“…37 However, TNF-␣ blockade is ineffective or even counterproductive in S. aureus-induced sepsis in humans. 38 These discrepancies warrant an animal model that better recapitulates the disease in humans.…”

mentioning

confidence: 99%

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Tilahun

Marietta

et al. 2011

The American Journal of Pathology

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“…Despite promising results of antiinflammatory interventions in animal models (4 -6) and human phase I and II trials (7,8), phase III clinical trials generally failed to show any success (9 -11) and in some cases even appeared detrimental (12). It has been postulated that the immune response in sepsis represents the interplay of two contrasting phenomena related to the inflammatory status of the septic patient.…”

mentioning

confidence: 99%

Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality

Osuchowski

Welch

Siddiqui

et al. 2006

The Journal of Immunology

456

369

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Mortality in sepsis remains unacceptably high and attempts to modulate the inflammatory response failed to improve survival. Previous reports postulated that the sepsis-triggered immunological cascade is multimodal: initial systemic inflammatory response syndrome (SIRS; excessive pro-, but no/low anti-inflammatory plasma mediators), intermediate homeostasis with a mixed anti-inflammatory response syndrome (MARS; both pro- and anti-inflammatory mediators) and final compensatory anti-inflammatory response syndrome (CARS; excessive anti-, but no/low proinflammatory mediators). To verify this, we examined the evolution of the inflammatory response during the early phase of murine sepsis by repetitive blood sampling of septic animals. Increased plasma concentrations of proinflammatory (IL-6, TNF, IL-1β, KC, MIP-2, MCP-1, and eotaxin) and anti-inflammatory (TNF soluble receptors, IL-10, IL-1 receptor antagonist) cytokines were observed in early deaths (days 1–5). These elevations occurred simultaneously for both the pro- and anti-inflammatory mediators. Plasma levels of IL-6 (26 ng/ml), TNF-α (12 ng/ml), KC (33 ng/ml), MIP-2 (14 ng/ml), IL-1 receptor antagonist (65 ng/ml), TNF soluble receptor I (3 ng/ml), and TNF soluble receptor II (14 ng/ml) accurately predicted mortality within 24 h. In contrast, these parameters were not elevated in either the late-deaths (day 6–28) or survivors. Surprisingly, either pro- or anti-inflammatory cytokines were also reliable in predicting mortality up to 48 h before outcome. These data demonstrate that the initial inflammatory response directly correlates to early but not late sepsis mortality. This multifaceted response questions the use of a simple proinflammatory cytokine measurement for classifying the inflammatory status during sepsis.

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“…In a study of the efficacy of etanercept in 141 patients with septic shock, there were 10 deaths among 33 patients in the placebo group (30% mortality), 9 deaths among 30 patients receiving lowdose etanercept (0.15 mg/kg body weight) (30% mortality), 14 deaths among 29 patients receiving intermediatedose etanercept (0.45 mg/kg body weight) (48% mortality), and 26 deaths among 49 patients receiving high-dose etanercept (1.5 mg/kg body weight) (53% mortality) (19). There were more gram-positive infectious causes of sepsis in the 3 etanercept groups compared with the placebo group, in addition to an increase in Pseudomonas aeruginosa infection in the group receiving 0.45 mg/kg of etanercept (P ϭ 0.08).…”

Section: Tnf␣ Inhibition and Sepsismentioning

confidence: 99%

Infections and anti–tumor necrosis factor α therapy

Ellerin¹,

Rubin²,

Weinblatt³

2003

Arthritis & Rheumatism

266

125

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Treatment of Septic Shock with the Tumor Necrosis Factor Receptor:Fc Fusion Protein

Abstract: In patients with septic shock, treatment with the TNFR:Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality.

Cited by 1,120 publications

References 46 publications

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality

Infections and anti–tumor necrosis factor α therapy

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