DEVELOPMENTAL BIOLOGY OF IMMUNO REGULATORY CYTOKINES

这一建议的总体目标是：1）利用基础科学 评估生产和利用调节机制的技术 在感染的胎儿和新生儿受试者中的免疫调节细胞因子， 和2）基于这种生物学，设计和测试新的基于生物素的 治疗患有传染病的新生儿。 研究 将通过四个阶段进行，每个阶段都有一个具体的目标。 它们是： 1)为了描述各种免疫调节剂的产生动力学， 来自各种类型的增殖细胞的细胞因子，以及在体内，来自 胎儿和新生小鼠以及胎儿和新生人。 我们最初 研究表明早产儿体内的巨噬细胞 产生的G-CSF和IL-6的量少于 巨噬细胞从成人，这是减少的结果， 转录。 2)为了确定减少产量的机制， 胎儿和新生小鼠和人类的某些细胞因子。 我们提出 两个备选假设：胎儿产精氨酸细胞 环境“编程”产生某些细胞因子以及其他 差，相对于胎儿产精氨酸细胞的内在缺陷。 建议进行研究，首先确定哪种替代方案 假设是正确的，第二，开始阐明负责 机制 3)目的：评价中药复方制剂对新生儿靶细胞的作用。 新生儿产生的特定细胞因子。 我们 维持某些细胞因子（如G-CSF）的减少产生， 受感染的胎儿受试者必须根据以下信息进行解释： 这些细胞因子对胎儿靶细胞的作用。 4)为了评估施用特异性细胞因子的效果， 由受感染的新生婴儿产生的不良，感染的新生小鼠， 新生的人类 新生儿细菌感染的实验动物模型 感染E.大肠杆菌和B群链球菌在我们的 实验室 此外，我们还开始了第一和第二阶段的试验， 将重组人G-CSF施用至感染的人新生儿。

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.