Summary of Work: Clinical experience with immunodulators in patients with sepsis has been disappointing to date. Tumor necrosis factor soluble receptor (TNFsr) is one such agent. In early preclinical work utilizing endotoxin or gram-negative bacteria infusion challenges, TNFsr was protective. However, in clinical sepsis trials by Immunex, this agent appeared harmful. These findings suggest that factors not yet identified may alter the effects of immunodulation with such agents. We have now demonstrated, using a multifactorial study design with a rat E. coli sepsis model, that site and severity of infection strongly influence the effects of G-CSF, a pro-inflammatory immunodulator. Using a similar multifactorial design, we have now found that TNFsr has beneficial effects regardless of site and severity of infection during E. coli infection. This suggested that other factors might influence the effectiveness of TNFsr. One such factor, suggested in a clinical study evaluating TNFsr, was bacteria type. TNFsr appeared to be efficacious with gram-negative bacteria, but harmful with gram-positive ones in retrospective analysis. We are therefore now studying the influence of a gram-positive bacterium (Staphylococcus aureus) on the effects of TNFsr in rats.