DEVELOPMENTAL BIOLOGY OF IMMUNO REGULATORY CYTOKINES

这项建议的总体目标是：1)利用基础科学 评估生产和利用调节机制的技术 免疫调节细胞因子在感染胎儿和新生儿中的作用， 2)基于这种生物学，设计和测试新的基于细胞因子的 新生儿感染性疾病的治疗。这些研究 将经历四个阶段，每个阶段都有一个具体的目标。 它们是： 1)描述各种免疫调节剂的产生动力学 来自各种类型的移植细胞的细胞因子，以及体内的细胞因子，来自 胎儿和新生小鼠，以及胎儿和新生儿的人类。我们最初的 研究表明，来自早产儿的移植巨噬细胞 产生的G-CSF和IL-6的量不到十分之一 来自成人的巨噬细胞，这是由于 抄写。 2)确定减产的机制 胎儿、新生小鼠和人类对某些细胞因子的影响。我们建议 两种可供选择的假设；胎儿细胞因子产生细胞是 在环境中“编程”产生某些细胞因子和其他细胞因子 糟糕的是，这是胎儿细胞因子产生细胞的固有缺陷。 建议进行的研究将首先确定哪种替代方案 假设是正确的，第二，开始阐明责任人 机制。 3)评估不同年龄组新生儿对靶细胞的作用。 新生儿产生的特定细胞因子很少。我们 通过以下方式维持某些细胞因子(如G-CSF)的减少 受感染的胎儿受试者必须根据 这些细胞因子对胎儿靶细胞的作用。 4)评估应用特定细胞因子的效果 由受感染的新生儿生产的很差，对受感染的新生小鼠和 新生的人类。新生儿细菌性感染的实验动物模型 感染大肠埃希菌和B组链球菌在我们的 实验室。此外，我们已经开始了第一阶段和第二阶段的试验 重组人粒细胞集落刺激因子在感染新生儿体内的应用

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.