COMBINATION IMMUNOTHERAPY WHICH NEUTRALIZES THE EFFECTS OF TNF-ALPHA AND IL-1-BETA ATTENUATES THE CIRCULATORY FAILURE AND MULTIPLE ORGAN DYSFUNCTION CAUSED BY ENDOTOXIN IN THE RAT

Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF a lpha) or interleukin-1 beta (IL-1 beta) are implicated in the pathogen esis of septic shock. Here we investigate the role of endogenous TNF a lpha and IL-1 beta on (i) the circulatory failure, (ii) the multiple o rgan dysfunction syndrome (MODS) and (iii) the induction of the induci ble isoform of nitric oxide (NO) synthase (iNOS) caused by endotoxin ( LPS) in the anaesthetised rat. Here we demonstrate that (i) a polyclon al antibody against TNF alpha, (ii) a polyclonal antibody against IL-1 , (iii) co-administration of polyclonal antibodies against TNF alpha a nd IL-1 and (iv) neutralisation of the effects of both TNF alpha and I L-I with one polyclonal antibody directed against both cytokines reduc es the circulatory failure, the liver injury/dysfunction, the pancreat ic injury (but not the renal dysfunction) caused by endotoxin in the r at. The beneficial effects of these interventions on haemodynamics and organ injury/dysfunction are most likely due to prevention of the ind uction of iNOS. The two different interventions which neutralised the effects of both TNF alpha and IL-1 were superior in reducing the circu latory failure and the organ injury caused by endotoxin in the rat, th an single interventions aimed at neutralising the effects of either cy tokine. Thus, we propose that interventions which are able to neutrali se the effects of both TNF alpha and IL-1 (combination immunotherapy) may be of benefit in the treatment of patients with septic shock.