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Experimental therapies for sepsis directed against tumour necrosis factor
1Department of Molecular and Genetic Medicine, University of Sheffield Medical School, UK. r.c.read@sheffield.ac.uk
Abstract:
Tumour necrosis factor (TNF) has been identified as an important mediator involved in the generation of sepsis syndrome. Two major strategies have evolved for counteracting the effects of TNF in patients with severe manifestations of sepsis: neutralization by anti-TNF antibodies and competitive antagonism of TNF with synthetic soluble TNF receptors. Clinical trials with murine monoclonal antibodies against TNF have shown that this agent is able to reduce early morbidity and mortality, but with no reduction in 28 day mortality. A clinical study with a synthetic 75 kDa soluble TNF receptor failed to show any benefit with this drug and indeed there was higher mortality at higher doses. Trials of a 55 kDa soluble TNF receptor are continuing and this drug is apparently safe. Drugs that modify TNF in vivo may be a useful component of future management of sepsis, either as monotherapy or as part of a combined strategy of immunomodulation.
Insights
Tumour necrosis factor (TNF) blockade strategies for sepsis show mixed results. While anti-TNF antibodies reduced early sepsis symptoms, soluble TNF receptors had limited success, necessitating further research into immunomodulatory treatments.
Area of Science:
- Immunology
- Sepsis Pathophysiology
- Pharmacology
Background:
- Tumour necrosis factor (TNF) is a key mediator in sepsis syndrome development.
- Current therapeutic strategies target TNF through antibody neutralization or receptor antagonism.
Purpose of the Study:
- To evaluate the efficacy of anti-TNF therapies in severe sepsis.
- To assess the safety and effectiveness of soluble TNF receptors in sepsis management.
Main Methods:
- Clinical trials involving murine monoclonal antibodies against TNF.
- Clinical studies utilizing synthetic 75 kDa and 55 kDa soluble TNF receptors.
Main Results:
- Anti-TNF antibodies reduced early sepsis morbidity and mortality but not 28-day mortality.
- The 75 kDa soluble TNF receptor showed no benefit and increased mortality at higher doses.
- The 55 kDa soluble TNF receptor appears safe in ongoing trials.
Conclusions:
- TNF-modifying drugs may be beneficial for sepsis management.
- Future sepsis treatment may involve TNF inhibitors as monotherapy or in combination immunomodulation strategies.