Immunomodulation of LPS ability to induce the local Shwartzman reaction.

Abstract

Immunologically, the septic shock is a natural model of immunomediated vascular pathology where the interaction between cytokines and the endothelium mediates the syndrome and lethality. Tumour necrosis factor (TNF), a non-species-specific cytokine, has outstanding pleiotropic activities as an important mediator of the septic shock syndrome. In rabbits, passive immunization with anti-lipopolysaccharide (LPS) polyclonal antibodies prior to the intravenous (i.v.) injection of LPS inhibits the haemorrhagic necrotic lesion characteristic of the local Shwartzman reaction (an excellent localized in vivo correlate of the septic shock). Paradoxically, tested in an ex vivo assay (short-term whole human blood culture, stimulated with LPS), these antibodies mediated an increase in TNF production by mononuclear phagocytes and, in the rabbit model, they induced an increase in body temperature, as compared with the pre-immune reagent. Although anchoring of immune complexes containing LPS to receptors (Fc or C4b-C3b) on circulating monocytes may facilitate the access of LPS to these cells, access to localized, LPS-sensitized macrophages may be impaired. Consequently inhibition of the local Shwartzman reaction and increased TNF production in the ex vivo system were observed. Concordantly, the higher temperature in the passively immunized animals may be a consequence of a higher, immune complex-induced, systemic TNF production. These experimental results suggest that the use of anti-LPS immunoglobulins, as a potential immunotherapy for septic shock syndrome in vertebrates, may lead to increased TNF production, with adverse effects such as the pyrogenic.