OBSERVATIONS ON THE ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN A MURINE MODEL OF SHOCK DUE TO STREPTOCOCCUS-PYOGENES

Objective: To examine the effect of a monoclonal antibody to tumor necrosis factor-alpha (TNF-alpha) in a murine model of shock due to Streptococcus pyogenes. Design: Prospective, multiexperimental, randomized, controlled trial. Setting: University hospital research laboratory. Interventions. An LD90 murine model of Gram-positive shock using S. pyogenes, associated with the presence of significant concentrations of TNF-alpha. in the circulation. Prophylactic administration of antibody with concomitant saline controls. A 500-mug TN3-19.12 (hamster monoclonal antibody to recombinant murine TNF), or saline, by intravenous injection was administered. Measurements and Main Results: Administration of 0.3 mL of 6 x 10(8) colony-forming units/mL of S. pyogenes H250 to mice resulted in 90% to 100% mortality rates in 72 hrs. Serum TNF-alpha concentrations peaked at 2 hrs after bacterial challenge and were 67.7 +/- 18.6 ng/mL. Treatment with anti-TNF-alpha monoclonal antibody abolished the serum TNF-alpha. concentrations but did not affect the mortality rate. Serum endotoxin concentrations were <50 pg/mL before challenge and at 0.5, 1, 2, 5, and 24 hrs after challenge. Conclusions. Pretreatment with an anti-TNF monoclonal antibody was not protective in this model of S. pyogenes sepsis, despite the presence of significant amounts of TNF in the circulation. These data suggest that TNF-alpha may not play such a crucial role in the pathogenesis of shock due to S. pyogenes.