title: Combination immunotherapy which neutralises the effects of TNF alpha and IL-1 beta attenuates the circulatory failure and multiple organ dysfunction caused by endotoxin in the rat.
abstract: Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF alpha) or interleukin-1 beta (IL-1 beta) are implicated in the pathogenesis of septic shock. Here we investigate the role of endogenous TNF alpha and IL-1 beta on (i) the circulatory failure, (ii) the multiple organ dysfunction syndrome (MODS) and (iii) the induction of the inducible isoform of nitric oxide (NO) synthase (iNOS) caused by endotoxin (LPS) in the anaesthetised rat. Here we demonstrate that (i) a polyclonal antibody against TNF alpha, (ii) a polyclonal antibody against IL-1, (iii) co-administration of polyclonal antibodies against TNF alpha and IL-1 and (iv) neutralisation of the effects of both TNF alpha and IL-1 with one polyclonal antibody directed against both cytokines reduces the circulatory failure, the liver injury/dysfunction, the pancreatic injury (but not the renal dysfunction) caused by endotoxin in the rat. The beneficial effects of these interventions on haemodynamics and organ injury/dysfunction are most likely due to prevention of the induction of iNOS. The two different interventions which neutralised the effects of both TNF alpha and IL-1 were superior in reducing the circulatory failure and the organ injury caused by endotoxin in the rat, than single interventions aimed at neutralising the effects of either cytokine. Thus, we propose that interventions which are able to neutralise the effects of both TNF alpha and IL-1 (combination immunotherapy) may be of benefit in the treatment of patients with septic shock.
authors.affiliation: William Harvey Research Institute, St. Bartholomew's School of Medicine, London, United Kingdom.
authors.forename: H
authors.initials: H
authors.lastname: Ruetten
authors.forename: C
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D001775:Blood Circulation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004926:Escherichia coli; D007375:Interleukin-1 / Q000276:immunology*; D008070:Lipopolysaccharides; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000628:therapy*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000906:Antibodies; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha