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

胎儿手术引起的母婴二元体的免疫反应以及与早产的关联

• 批准号: 10113537
• 负责人: Elizabeth Ann Lieser Enninga
• 金额: $ 23.83万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-24 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113537
• 关键词: 37 weeks gestation; 5 year old; Acute; Address; Adrenal Cortex Hormones; Allogenic; Animal Model; Animals; Antigens; Aspirin; Biological Markers; Birth; Blood; Cause of Death; Cells; Child; Clinic; Clonal Expansion; Clone Cells; Congenital Abnormality; Congenital diaphragmatic hernia; Cytometry; Data; Diagnosis; Diagnostic Imaging; Dose; Early Intervention; Effectiveness; Enrollment; Ethnic Origin; Exhibits; Fetal Development; Fetus; Functional disorder; Future; Genetic Materials; Gestational Age; Guidelines; Histology; Human; IL2RA gene; Immune; Immune Tolerance; Immune response; Immune system; Infant; Inflammation; Inherited; Interleukin-6; Intervention; Lead; Length; Life; Lower urinary tract; Macrophage Activation; Maternal Age; Maternal-Fetal Exchange; Maternal-fetal medicine; Maternally-Acquired Immunity; Measures; Mediating; Meningomyelocele; Methods; Microchimerism; Modality; Mothers; Neonatal; Newborn Infant; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Outcome; Outcomes Research; Pharmaceutical Preparations; Phenotype; Placenta; Pregnancy; Pregnancy Outcome; Premature Birth; Premature Infant; Premature Labor; Prevention; Procedures; Process; Regulation; Reproduction; Research Personnel; Risk; Sampling; Spinal Dysraphism; T-Cell Activation; T-Lymphocyte; TNFSF5 gene; Testing; Therapeutic; Time; Translating; Trauma; Umbilical Cord Blood; United States; Virus Diseases; Woman; Work; alpha-Fetoproteins; base; clinical care; cohort; congenital anomaly; design; diagnostic technologies; drug testing; embryo surgery; embryo/fetus antigen; experimental study; fetal; fetus cell; fetus surgery; immune activation; immunomodulatory strategy; improved; in utero; macrophage; mouse model; neonate; parity; premature; prenatal exposure; prevent; repaired; response; sex; therapeutically effective; treatment duration; trophoblast; urinary tract obstruction

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.

全世界有30多万新生儿在出生后第一个月内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，胎儿手术领域的发展是为了治疗一些 子宫内的情况结果表明，在以下情况下， 手术，特别是对于那些被诊断为先天性膀胱疝，下尿路 梗阻和脊柱裂。然而，超过30%的手术病例会有早产，导致 与新生儿早产有关的并发症。这种手术引起的早产的原因尚不清楚; 然而，胎儿-母体耐受性的破坏可能导致免疫激活和炎症， 母亲和胎儿的免疫系统。在怀孕期间维持免疫耐受是必不可少的， 女性只有一半的遗传物质与胎儿相同。以前的研究表明，胎儿 手术导致在脐带血中鉴定的母体细胞增加。动物研究也表明， 子宫干预导致母细胞针对胎儿（父）抗原的活化。基于此 根据先前的数据，我们假设子宫内干预后的手术创伤导致母体 和胎儿细胞，导致系统性（适应性母体免疫）和区域性（胎儿胎盘免疫）的激活。 巨噬细胞）免疫反应，破坏胎儿-母体耐受性，这可能导致早产。 这些假设将在以下特定目的的实验中解决：1）确定对胎儿抗原特异性的母体T细胞是否在子宫内干预后被激活和扩增;和2）确定与足月相比，在早产（<37周）的手术病例中，胎盘巨噬细胞（霍夫鲍尔细胞）和母胎界面中的组织学是否表现出增加的激活和炎症。如果该探索性研究显示子宫内手术后母体和/或胎儿免疫应答的激活，则旨在治疗性抑制这些急性应答的方法可能会延长妊娠期，从而使诊断为先天性异常的新生儿显著受益。

项目成果

Fetal surgery is not associated with increased inflammatory placental pathology.

胎儿手术与炎症性胎盘病理的增加无关。

• DOI: 10.1002/pd.6319
• 发表时间: 2023
• 期刊: Prenatal diagnosis
• 影响因子: 3
• 作者: Cardenas,MariaC;Cheek-Norgan,EHeidi;Branda,MeganE;Norgan,AndrewP;Schenone,MauroH;Lemens,MaureenA;Chakraborty,Rana;Ruano,Rodrigo;Enninga,ElizabethAnnL
• 通讯作者: Enninga,ElizabethAnnL