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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Physician Scientist Award (K11)
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Maternal and Child Health Research Committee (HDMC)
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Schibler, K R; Osborne, K A; Leung, L Y et al. (1998) A randomized, placebo-controlled trial of granulocyte colony-stimulating factor administration to newborn infants with neutropenia and clinical signs of early-onset sepsis. Pediatrics 102:6-13
Ohls, R K; Harcum, J; Schibler, K R et al. (1997) The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr 131:661-5
Le, T; Leung, L; Carroll, W L et al. (1997) Regulation of interleukin-10 gene expression: possible mechanisms accounting for its upregulation and for maturational differences in its expression by blood mononuclear cells. Blood 89:4112-9
Schibler, K R; Li, Y; Ohls, R K et al. (1994) Possible mechanisms accounting for the growth factor independence of hematopoietic progenitors from umbilical cord blood. Blood 84:3679-84
Liechty, K W; Schibler, K R; Ohls, R K et al. (1993) The failure of newborn mice infected with Escherichia coli to accelerate neutrophil production correlates with their failure to increase transcripts for granulocyte colony-stimulating factor and interleukin-6. Biol Neonate 64:331-40
Schibler, K R; Liechty, K W; White, W L et al. (1993) Production of granulocyte colony-stimulating factor in vitro by monocytes from preterm and term neonates. Blood 82:2478-84
Schibler, K R; Trautman, M S; Liechty, K W et al. (1993) Diminished transcription of interleukin-8 by monocytes from preterm neonates. J Leukoc Biol 53:399-403