Clinical experience with immunomodulators in patients with sepsis have been disappointing to date. Tumor necrosis factor soluble receptor (TNFsr) is one such agent. In early preclinical work utilizing endotoxin or 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 immunomodulation 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 immunomodulator. Once studies are completed characterizing factors which influence G-CSF's effects, we plan to use this same model and experimental design to study factors potentially influencing the effects of TNFsr. Initial studies will evaluate site and severity of infection, and dose of drug. These studies are being done in collaboration with Dr. Janice Augusti from the Immunex company.