The overall objectives of this proposal are: 1) to use basic science techniques to assess the mechanisms regulating production and utilization of immunoregulatory cytokines in infected fetal and neonatal subjects, and 2) based on this biology, to devise and test new cytokine-based treatments for newborn infants with infectious diseases. The studies will proceed through four stages, each represented by a specific aim. They are: 1) To describe the kinetics of production of various immunoregulatory cytokines from explanted cells of various types, as well as in vivo, from fetal and newborn mice and from fetal and newborn humans. Our initial studies indicate that explanted macrophages from preterm neonates generate less than 1/10th the quantities of G-CSF and IL-6 as do macrophages from adults, and that this is the result of decreased transcription. 2) To determine the mechanism responsible for the diminished production of certain cytokines by fetal and newborn mice and humans. We propose two alternative hypotheses; that fetal cytokine-producing cells are environmentally """"""""programmed"""""""" to produce certain cytokines well and others poorly, vs an intrinsic defect in fetal cytokine-producing cells. Studies are proposed that will first, determine which of the alternative hypotheses is correct and second, begin to elucidate the responsible mechanism. 3) To assess the actions on target cells from newborn infants of the specific cytokines that are produced poorly by newborn infants. We maintain that reduced production of certain cytokines (such as G-CSF) by infected fetal subjects must be interpreted in light of information on the action of such cytokines on fetal target cells. 4) To assess the effect of administering the specific cytokines that are produced poorly by infected newborn infants, to infected newborn mice and newborn humans. Experimental animal models of neonatal bacterial infection with E. coli and group B streptococcus are in use in our laboratory. In addition, we have begun phase I and II trials of administration of recombinant human G-CSF to infected human neonates.
