Maternal Central Immune Tolerance in Reproduction

母体生殖中枢免疫耐受

• 批准号: 10617856
• 负责人: MARGARET G PETROFF
• 金额: $ 39.96万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-13 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617856
• 关键词: Adult; Allografting; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Cells; Data; Diagnosis; Disease; Embryo; Embryo Loss; Embryo Transfer; Ensure; Estrogens; Fertility; Fetal Growth Retardation; Fetus; Foundations; Gene Expression; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Gonadal structure; Gravid; Hormones; Immune; Immune Tolerance; Immune system; Immunologic Surveillance; Immunosuppression; In Vitro; Infertility; Inherited; Knockout Mice; Knowledge; Link; Malignant Neoplasms; Maps; Maternal-Fetal Exchange; Mediating; Mus; Oocytes; Ovarian; Ovary; Peripheral; Personal Satisfaction; Physiological; Placenta; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy loss; Premature Birth; Prevention strategy; Process; Progesterone; Progesterone Receptors; Proteins; Regulation; Regulatory T-Lymphocyte; Reporting; Reproduction; Reproductive Health; Reproductive system; Research; Role; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Time; Tissues; Transplantation Immunology; Uterus; Woman; Work; age related; base; blastocyst; central tolerance; combat; embryo quality; embryo/fetus antigen; embryonic stem cell; experimental study; failure Implantation; female fertility; fetal; fetal loss; healthy pregnancy; immune function; implantation; in vivo; in vivo Model; insight; intimate behavior; maternal immune system; mouse model; natural Blastocyst Implantation; novel; pregnancy disorder; progesterone receptor A; reproductive; reproductive function; reproductive outcome; reproductive tract; societal costs; transcription factor; tumor immunology

The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which antigenically unique, tissue-specific proteins are introduced to the mother’s immune system at the commencement and for the duration of pregnancy. When this tolerance fails, infertility, preterm birth and delivery, preeclampsia, or fetal growth restriction may result. Aire is a transcriptional regulator that induces expression of tissue-restricted genes in the thymus, wherein central tolerance to many self-antigens is acquired. Aire ensures that tolerance to such antigens is established in developing T cells. Tissue-restricted genes regulated by Aire include many that are specific to the fetus and placenta, and we have found not only that Aire is upregulated in the thymus during pregnancy, but also that global Aire deficiency can predispose dams to fetal loss. Intriguingly, our group and others have also identified Aire expression in the ovary and uterus, suggesting an additional, extrathymic role of this transcription factor. In this project, we aim to define the role of Aire in immune tolerance to the fetus, elucidate its regulation by sex hormones, and clarify its immune- independent role in reproduction. We will test the overall hypothesis that Aire is required for central immune tolerance the fetus, and that it functions in parallel within the uterus and ovary to support fertility. We propose two specific aims: Aim 1. Determine the impact of Aire deficiency on maternal immune tolerance to the fetus. Aim 2. Ascertain the functional connection between sex hormones and Aire in maternal central tolerance to the fetus. Aim 3. Identify the immune-independent function of Aire in female fertility. The results of these experiments are expected to provide highly novel insight into as-yet unexplored mechanisms of maternal tolerance to the fetal-placental unit, female fertility, and the regulation thereof by sex hormones, greatly advancing our understanding of maternal tolerance to the fetal allograft. The results will have far-reaching implications for women’s wellbeing in the fields of pregnancy, reproductive health, autoimmune disease, transplantation, and cancer immunology.

本研究的总体目标是了解妊娠期母体对胎儿的免疫耐受机制。母体免疫系统和胎儿同种异体移植物之间的密切关系是一种无与伦比的生理状况，在这种情况下，抗原独特的组织特异性蛋白质在妊娠开始时和妊娠期间被引入母体的免疫系统。当这种耐受性失败时，可能会导致不孕、早产和分娩、先兆子痫或胎儿生长受限。 Aire 是一种转录调节因子，可诱导胸腺中组织限制性基因的表达，其中获得了对许多自身抗原的中枢耐受性。 Aire 确保在发育中的 T 细胞中建立对此类抗原的耐受性。 Aire 调节的组织限制性基因包括许多胎儿和胎盘特有的基因，我们发现不仅 Aire 在怀孕期间在胸腺中表达上调，而且整体 Aire 缺乏会使母鼠容易流产。有趣的是，我们的小组和其他人还发现了 Aire 在卵巢和子宫中的表达，这表明该转录因子具有额外的胸腺外作用。在这个项目中，我们的目标是定义 Aire 在胎儿免疫耐受中的作用，阐明其通过性激素的调节，并阐明其在生殖中的免疫独立作用。我们将检验以下总体假设：Aire 是胎儿中枢免疫耐受所必需的，并且它在子宫和卵巢内并行发挥作用以支持生育能力。我们提出了两个具体目标： 目标 1. 确定艾尔缺陷对母体对胎儿免疫耐受的影响。目标 2. 确定性激素和艾尔在母体对胎儿的中枢耐受性中的功能联系。目标 3. 确定 Aire 在女性生育能力中的免疫独立功能。这些实验的结果预计将为尚未探索的母体对胎儿胎盘单位的耐受性、女性生育能力以及性激素的调节机制提供高度新颖的见解，从而极大地增进我们对母体对胎儿同种异体移植物的耐受性的理解。研究结果将对怀孕、生殖健康、自身免疫性疾病、移植和癌症免疫学领域的女性福祉产生深远影响。

项目成果

Fetal-placental antigens and the maternal immune system: Reproductive immunology comes of age.

• DOI: 10.1111/imr.13090
• 发表时间: 2022-07
• 期刊: Immunological reviews
• 影响因子: 8.7

Nuclear Progesterone Receptor Expressed by the Cortical Thymic Epithelial Cells Dictates Thymus Involution in Murine Pregnancy.

• DOI: 10.3389/fendo.2022.846226
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Ahn, Soo Hyun;Nguyen, Sean L.;Kim, Tae Hoon;Jeong, Jae-Wook;Arora, Ripla;Lydon, John P.;Petroff, Margaret G.
• 通讯作者: Petroff, Margaret G.

Production and Composition of Group B Streptococcal Membrane Vesicles Vary Across Diverse Lineages.

• DOI: 10.3389/fmicb.2021.770499
• 发表时间: 2021
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: McCutcheon CR;Pell ME;Gaddy JA;Aronoff DM;Petroff MG;Manning SD
• 通讯作者: Manning SD