DOSAGE AND TIMING OF ANTI-TNF-ALPHA ANTIBODY TREATMENT DETERMINE ITS EFFECT ON RESISTANCE TO SEPSIS AFTER INJURY

Antibody against tumor necrosis factor-alpha (TNF-alpha) has improved survival in certain models of sepsis, but it remains unproven in clini cal studies. In most of the successful animal studies, efficacy has be en shown in previously healthy animals subjected to a septic challenge . Patients at risk for sepsis, however, may be ill for some time befor e the sepsis supervenes. This situation has been described as a ''two- hit'' model of critical illness. We have developed an animal burn-seps is model which conforms to this ''two-hit'' concept. We have quantifie d macrophage TNF-alpha production at different times after the burn (f irst ''hit'') and determined the effect of neutralizing antibody again st TNF-alpha during this period on survival after subsequent sepsis (s econd ''hit''). The objective of this study was to determine the role of TNF-alpha and the effect of neutralizing antibody against TNF-alpha in a burn-sepsis model, Animals were subjected to a full thickness bu rn or sham burn. In vibro TNF-alpha production from cultured lipopolys accharide-stimulated splenic adherent cells was determined at various time points thereafter by enzyme-linked immunosorbent assay. Separate animals were treated with neutralizing antibody against TNF-alpha at d ifferent time points after the thermal injury, and survival was determ ined after septic challenge (cecal ligation and puncture) on Day 10 af ter the burn. TNF-alpha production from adherent splenocytes was not e levated in the early days after thermal injury, but was significantly enhanced from Day 6 onward compared with sham-burned animals. Nine per cent of the burned mice survived septic challenge compared with 69% of the sham-burned control mice (P < 0.001). Therapy with anti-TNF antib ody at 1 x 10(4) neutralizing units (n.u.) kg(-1) markedly improved ou tcome if given when TNF-alpha production was elevated at Day 7 after t he burn (survival, 36%; P = 0.01) but did not improve survival when ad ministered at Days 0 or 4 or at the time of the septic challenge (Day 10), High doses of antibody (3.2 x 10(5) n.u.kg(-1)) were not benefici al and may have been detrimental. These results show that neutralizing antibody against TNF-alpha may reduce the susceptibility to infection seen after thermal injury, but the timing of administration of the an tibody and the dose of antibody used are critical to the outcome. This should be considered when neutralizing antibody against TNF is used i n the clinical setting. (C) 1996 Academic Press, Inc.