Clinical experience with immunomodulators in patients with sepsis has been disappointing to date. Tumor necrosis factor soluble receptor (TNFsr) is one such immunomodulator. In early preclinical work using endotoxin or Gram-negative bacteria infusion challenges, TNFsr was protective. However, in clinical sepsis trials by Immunex, it appeared harmful. These findings suggest that factors not yet identified may alter the effects of immunomodulation with such agents. Using a multifactorial study design with a rat Escherichia coli sepsis model, we have now demonstrated that site and severity of infection strongly influence the effects of granulocyte colony- stimulating factor, a pro-inflammatory immunomodulator. With a similar multifactorial design, we have found that TNFsr has beneficial effects regardless of site and severity of infection. This finding suggests that other factors might influence the effectiveness of TNFsr. One such factor suggested in the clinical study evaluating TNFsr was bacteria type. TNFsr in retrospective analysis appeared to be efficacious with Gram-negative bacteria but potentially harmful with Gram-positive ones. We therefore plan to study the influence of either a Gram-positive bacteria (S. aureus) or a Gram-negative bacteria (E. coli) on the effects of TNFsr in rats. Performance of these studies will be dependent on a supply of TNFsr we hope will be provided by Dr. Janice Augusti of Immunex.