Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis
Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis
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DOI：
10.1128/iai.01235-12
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发表时间：
2013-05-01
影响因子：
3.1
通讯作者：
Wege, Anja K.
中科院分区：
文献类型：
--
作者：
Ernst, Wolfgang;Zimara, Nicole;Wege, Anja K.
B族链球菌（GBS）的细菌感染代表了西方世界中对新生儿和胎儿的突出威胁，导致严重的器官损伤甚至死亡。为了改善目前的治疗策略和研究新的方法，需要一种合适的体内模型来研究人类免疫系统的免疫应答。因此，我们引入人源化小鼠作为GBS诱导的脓毒症的新模型。人源化小鼠具有与新生儿中发现的缺陷相似的缺陷，例如较低的免疫球蛋白水平和骨髓细胞功能障碍。由于在无特定病原体（SPF）设施中饲养，这些小鼠中的人免疫细胞也表现出模拟胎儿/新生儿条件的幼稚表型。感染后，细胞因子释放和白细胞从骨髓运输到淋巴器官（脾）并进入腹膜（感染部位）以及细菌扩散和清除在人源化小鼠中可追踪。此外，我们使用这种新的脓毒症模型研究了倍他米松和吲哚美辛治疗的效果。虽然这两种药物通常用于围产期护理，但对它们对新生儿免疫系统的影响知之甚少。感染的人源化小鼠的治疗不仅诱导脾中人白细胞的减少，而且还增加了所有分析器官（包括脑）中的细菌负荷，其在未治疗的对照中未显示活GBS的浸润。这些研究证明了人源化小鼠作为研究细菌感染期间不成熟的人类免疫应答的新模型的实用性，并允许研究由各种治疗诱导的副作用。
Bacterial infection with group B Streptococcus (GBS) represents a prominent threat to neonates and fetuses in the Western world, causing severe organ damage and even death. To improve current therapeutic strategies and to investigate new approaches, an appropriate in vivo model to study the immune response of a human immune system is needed. Therefore, we introduced humanized mice as a new model for GBS-induced sepsis. Humanized mice feature deficiencies similar to those found in neonates, such as lower immunoglobulin levels and myeloid cell dysfunction. Due to the husbandry in specific-pathogen-free (SPF) facilities, the human immune cells in these mice also exhibit a naive phenotype which mimics the conditions in fetuses/neonates. Following infection, cytokine release and leukocyte trafficking from the bone marrow to the lymphoid organ (spleen) and into the peritoneum (site of infection) as well as bacterial spreading and clearance were traceable in the humanized mice. Furthermore, we investigated the effects of betamethasone and indomethacin treatment using this novel sepsis model. Although both drugs are commonly used in perinatal care, little is known about their effects on the neonatal immune system. Treatment of infected humanized mice not only induced the reduction of human leukocytes in the spleen but also increased the bacterial load in all analyzed organs, including the brain, which did not show infiltration of live GBS in untreated controls. These studies demonstrate the utility of the humanized mice as a new model to study an immature human immune response during bacterial infection and allow the investigation of side effects induced by various treatments.