Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia

Abstract

Bacterial infection of the mammalian bloodstream can lead to overwhelming sepsis, a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure. Cachectin, also known as tumour necrosis factor, is a macrophage-derived peptide hormone released in response to bacterial lipopolysaccharide, and it has been implicated as a principal mediator of endotoxic shock, although its function in bacterial sepsis is not known. Anaesthetized baboons were passively immunized against endogenous cachectin and subsequently infused with an LD100 dose of live Escherichia coli. Control animals (not immunized against cachectin) developed hypotension followed by lethal renal and pulmonary failure. Neutralizing monoclonal anti-cachectin antibody fragments (F(ab')2) administered to baboons only one hour before bacterial challenge protected against shock, but did not prevent critical organ failure. Complete protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion. These results indicate that cachectin is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin offer a potential therapy of life-threatening infection.

Comparison of the effects of recombinant interleukin 6 and recombinant interleukin 1 on nonspecific resistance to infection

“…It is assumed that cytokines like TNF and IL 1 contribute to death from infection [18][19][20]. It could well be that early treat ment with IL 1, and to a much lesser extent with IL 6, reduces the lethal effects of these cytokines.…”

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

“…During the last 2 decades, TNF has been implicated in numerous diseases such as arthritis, 17 Alzheimer disease, 28 cancer, 29 major depression, 30 septic shock, 31 and inflammatory bowel disease. 32 Therefore, anti-TNF therapy has been used in clinical practice.…”

Is the septic response good or bad?

“…Anti-TNF-treatment reduces mortality in primate models of overwhelming sepsis induced by intravenous administration of bacteria [11]. In addition, neutralization of IL-1 also reduced lethality in animal models of sepsis [12].…”