Experimental therapies for sepsis directed against tumour necrosis factor

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.