IMMUNE RESPONSES IN THE MOTHER-INFANT DYAD INDUCED BY FETAL SURGERY, AND ASSOCIATIONS WITH PREMATURITY

全世界有超过30万新生儿在出生后的第一个月死于先天性出生缺陷。感谢 随着诊断技术和成像技术的进步，胎儿外科领域的发展是为了治疗一些 这些在子宫内的情况。结果表明，在以下情况下，短期和长期结果有所改善 外科手术，尤其是对诊断为先天性下尿路、横隔疝的胎儿 梗阻和脊柱裂。然而，超过30%的手术病例将会早产，导致 与新生儿早产相关的并发症。手术导致早产的原因尚不清楚； 然而，母胎耐受性的破坏可能会导致免疫激活和 母体和胎儿免疫系统。在怀孕期间保持免疫耐受是必不可少的，因为 女性只与胎儿分享了一半的遗传物质。之前的研究已经证明，胎儿 手术导致脐带血中确认的母体细胞增加。动物研究也表明，在 子宫干预导致母体细胞被激活以对抗胎儿(父系)抗原。在此基础上 以前的数据，我们假设宫内干预后的手术创伤导致母体混合 和胎儿细胞激活全身性(适应性母体免疫)和区域性(胎儿胎盘 巨噬细胞)破坏胎儿-母体耐受性的免疫反应，可能导致早产。 这些假设将在以下特定目标的实验中得到解决：1)确定子宫内干预后，母体针对胎儿抗原的T细胞是否被激活和扩张；2)确定胎盘巨噬细胞(Hofbauer细胞)和母胎界面的组织学是否显示出与足月相比早产(37周)的外科病例中更多的激活和炎症。如果这项探索性研究揭示了子宫手术后母体和/或胎儿免疫反应的激活，旨在从治疗上抑制这些急性反应的方法可能会延长妊娠，极大地有利于被诊断为先天性异常的新生儿。

Over 300,000 neonates worldwide die in their first month of life due to a congenital birth defect. Thanks to advancements in diagnostic technology and imaging, the field of fetal surgery was developed to treat some of these conditions in utero. Results have demonstrated improved short and long-term outcomes following surgery, especially for those fetuses diagnosed with congenital diaphragmatic hernia, lower urinary tract obstruction and spina bifida. However, over 30% of the surgical cases will have preterm labor, leading to complications related to neonatal prematurity. The cause of this surgery-induced preterm birth is unknown; however, disruption in fetal-maternal tolerance may lead to immune activation and inflammation of the maternal and fetal immune systems. Maintaining immunologic tolerance is essential during pregnancy, as a women shares only half of her genetic material with the fetus. Previous work has demonstrated that fetal surgery leads to an increase in maternal cells identified in cord blood. Animal studies have also shown that in utero intervention leads to the activation of maternal cells against fetal (paternal) antigen. Based on this previous data, we hypothesize that surgical trauma following in utero intervention results in mixing of maternal and fetal cells leading to activation of systemic (adaptive maternal immunity) and regional (fetal placental macrophages) immune responses that disrupt fetal-maternal tolerance, which can result in preterm birth. These hypotheses will be addressed in the experiments of the following Specific Aims: 1) to determine whether maternal T cells specific to fetal antigen are activated and expand after in utero intervention; and 2) to determine whether placental macrophages (Hofbauer Cells) and histology in the maternal-fetal interface exhibit increased activation and inflammation in surgical cases born preterm (<37 weeks) compared to term. Should this exploratory study reveal activation of maternal and/or fetal immune responses following in utero surgery, modalities aimed at therapeutically suppressing these acute responses may prolong gestation, significantly benefiting newborns diagnosed with a congenital anomaly.