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.


METHODS
Prospective, multiexperimental, randomized, controlled trial.


METHODS
University hospital research laboratory.


METHODS
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-micrograms TN3-19.12 (hamster monoclonal antibody to recombinant murine TNF), or saline, by intravenous injection was administered.


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.
Wayte
J
J
Department of Infectious Diseases and Bacteriology, Hammersmith Hospital, London, UK.
Silva
A T
AT
Krausz
T
T
Cohen
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001681:Biological Assay; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004731:Endotoxins / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D007262:Infusions, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011292:Premedication; D011897:Random Allocation; D012772:Shock, Septic / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D013290:Streptococcal Infections / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D013297:Streptococcus pyogenes; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects / Q000493:pharmacokinetics / Q000502:physiology*
D000911:Antibodies, Monoclonal; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha