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.

由于先天性出生缺陷，全球超过30万名新生儿死亡。由于 诊断技术和成像方面的进步，开发了胎儿手术领域，以治疗一些 这些条件在子宫内。结果表明，遵循的短期和长期结局得到了改善 手术，特别是对于那些被诊断为先天性diaphragm疝的胎儿，尿路较低 阻塞和脊柱裂。但是，超过30％的手术病例将有早产，导致 与新生儿早产相关的并发症。这种手术引起的早产的原因尚不清楚。 然而，胎儿母性耐受性的破坏可能导致免疫激活和炎症 母体和胎儿免疫系统。在怀孕期间维持免疫耐受性至关重要，作为一个 妇女与胎儿只有一半的遗传物质。以前的工作证明了胎儿 手术导致脐带血中鉴定出的母体细胞的增加。动物研究还表明 子宫干预导致母体细胞对胎儿（父亲）抗原的激活。基于此 先前的数据，我们假设在子宫干预中进行手术创伤导致母体混合 胎儿细胞导致全身性（适应性母体免疫）和区域（胎儿胎盘）激活 巨噬细胞）免疫反应，破坏胎儿女性耐受性，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）确定在子宫干预后是否激活了针对胎儿抗原的母体T细胞并扩展； 2）确定母亲界面中的胎盘巨噬细胞（Hofbauer细胞）和组织学在与期限相比出生的早产（<37周）中是否表现出增加的激活和炎症。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，旨在治疗抑制这些急性反应的方式可能会延长妊娠，从而使诊断为先天性异常的新生儿受益匪浅。

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