Trophoblast MHC-I: Trigger for Immune-Mediated Rejection of Cloned Bovine Fetuses

滋养层 MHC-I：克隆牛胎儿免疫介导排斥反应的触发因素

• 批准号: 8133153
• 负责人: CHRISTOPHER Joseph DAVIES
• 金额: $ 22.67万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133153
• 关键词: Aborted Fetus; Address; Allografting; Animal Model; Artificial Insemination; Assisted Reproductive Technology; Biology; Cattle; Cells; Clinical; Collection; Communication; Conceptus; Data; Development; Down-Regulation; Embryo; Embryo Transfer; Environment; Epithelial; Event; Exhibits; Failure; Fertilization; Fertilization in Vitro; Fetal Mortality Statistics; Fetus; First Pregnancy Trimester; Frequencies; Gene Expression; Gene Expression Regulation; Genes; Goals; Health; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; In Vitro; Incidence; Lead; Leukocytes; Lymphocyte; MHC Class I Genes; Maintenance; Major Histocompatibility Complex; Mammals; Mediating; Medicine; Modeling; Molecular; Mothers; Outcome; Pattern; Placenta; Placental Insufficiency; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Maintenance; Pregnancy Proteins; Probability; Proteins; Regulation; Research; Signal Transduction; Spontaneous abortion; Syndrome; T-Lymphocyte; Testing; Third Pregnancy Trimester; Tissues; Uterus; Woman; Work; abortion; base; drug production; fetal; functional genomics; improved; insight; mortality; novel strategies; prevent; reproductive; research study; somatic cell nuclear transfer; success; trophoblast

DESCRIPTION (provided by applicant): Immune-mediated abortion is an important, although poorly understood and often unrecognized, cause of pregnancy failure in women. Both spontaneous abortion and preeclampsia, which is associated with abnormal placentation, occur at increased frequency in human and bovine pregnancies established by assisted reproductive technologies such as in vitro fertilization (IVF). Our long-term goals are to understand the immunological basis of immune-mediated abortion and placental insufficiency, and to develop and test strategies to down-regulate the immune response to the conceptus. A unique bovine model of immune- mediated abortion and placental insufficiency based on the routine occurrence of inadequate placental development and fetal loss in bovine somatic cell nuclear transfer (SCNT) pregnancies will be used. Several observations support the validity of this model: (1) placental trophoblast cells of SCNT fetuses, in contrast to control fetuses, express classical major histocompatibility complex class I (MHC-I) antigens early in pregnancy, (2) T lymphocytes accumulate in the uterine stroma of SCNT recipients, and (3) MHC homozygous SCNT fetuses fare better than MHC heterozygous fetuses. These findings suggest that much of the fetal loss in SCNT pregnancies is due to immune-mediated abortion. This project is based on the general hypothesis that inappropriate trophoblast MHC-I expression early in pregnancy will induce immune-mediated abortion or placental insufficiency. Inappropriate expression of MHC-I proteins may consist of increased expression of classical MHC-I proteins, decreased expression of non-classical MHC-I proteins or a combination of the two. The proposal's specific aims are: (1) produce 8-10 MHC-I compatible SCNT, 8-10 MHC-I incompatible SCNT and 8-10 control pregnancies for collection of uterine and placental tissues on days 32 to 34 of pregnancy, and compare trophoblast MHC-I expression, uterine leukocyte populations and uterine and placental gene expression in the three types of pregnancies; and (2) compare embryonic mortality rates of SCNT embryos transferred into MHC-I compatible and incompatible recipient cows to determine if immune-mediated abortion can be avoided by eliminating the antigenic, MHC-I trigger. This project will elucidate the functional genomics of the cross-talk between the placenta and uterine immune system in normal and abnormal pregnancies. Functional genomics and morphological data will be integrated to create a complete picture of the cellular and molecular events involved in an important clinical problem: immune-mediated abortion. The project will also directly test the hypothesis that abnormal MHC-I expression early in pregnancy triggers immune-mediated abortion, a long-standing hypothesis that has never been adequately tested because of lack of a suitable animal model. PUBLIC HEALTH RELEVANCE: A mammalian conceptus must convince its mother's immune system to accept it. When the fetus fails to induce maternal tolerance, the outcome is either immune-mediated abortion or the development of abnormal placentation that can result in problems later in pregnancy. The incidence of immune-mediated abortion and placental insufficiency in both humans and cattle are greatly increased with the use of assisted reproductive technologies such as in vitro fertilization. In this study bovine somatic cell nuclear transfer pregnancies, which normally have a high rate of first trimester spontaneous abortions, will be used to study how communications between the conceptus and maternal immune system break down when embryos are manipulated in vitro.

描述（由申请人提供）：免疫介导的流产是一个重要的，尽管对女性的妊娠失败的理解且经常未被认可。与异常胎盘相关的自发流产和先兆子痫，在辅助生殖技术（例如体外受精（IVF））建立的人类和牛妊娠中的频率增加。我们的长期目标是了解免疫介导的堕胎和胎盘不足的免疫学基础，并制定和测试策略以下调对概念的免疫反应。基于常规发生胎盘发育不足的胎盘发育和胎儿损失，将使用牛体细胞核转移（SCNT）妊娠的常规发生，这是一种免疫介导的流产和胎盘不足的独特牛模型。几种观察结果支持该模型的有效性：（1）与对照胎儿相反，SCNT胎儿的胎盘滋养细胞细胞表达了经典的主要组织相容性复合物I类（MHC-I）抗原在妊娠早期抗原，（2）T淋巴细胞在SCNT受体中积累的scnt scnt和（3）MHC HYC的型号MHC型号的MHC型HYCTY HYCY HYCTY HYST型淋巴细胞积累胎儿。这些发现表明，SCNT妊娠的大部分胎儿丧失是由于免疫介导的流产所致。该项目基于一个普遍的假设，即怀孕早期的不适当滋养细胞MHC-I表达将诱导免疫介导的流产或胎盘不足。 MHC-I蛋白的不当表达可能包括经典MHC-I蛋白的表达增加，非经典MHC-I蛋白的表达降低或两者的组合。 The proposal's specific aims are: (1) produce 8-10 MHC-I compatible SCNT, 8-10 MHC-I incompatible SCNT and 8-10 control pregnancies for collection of uterine and placental tissues on days 32 to 34 of pregnancy, and compare trophoblast MHC-I expression, uterine leukocyte populations and uterine and placental gene expression in the three types of pregnancies; （2）比较转移到MHC-I兼容和不兼容的接受者奶牛中的SCNT胚胎的胚胎死亡率，以确定是否可以通过消除抗原，MHC-1触发器来避免免疫介导的流产。该项目将阐明正常和异常妊娠中胎盘和子宫免疫系统之间的跨语的功能基因组学。功能基因组学和形态数据将集成，以创建重要的临床问题所涉及的细胞和分子事件的完整图片：免疫介导的流产。该项目还将直接检验以下假设：妊娠早期的MHC-I异常表达触发免疫介导的流产，这是一个长期存在的假设，由于缺乏合适的动物模型，该假设从未得到充分检验。公共卫生相关性：哺乳动物的概念必须说服其母亲的免疫系统接受它。当胎儿无法诱导母体耐受性时，结果是免疫介导的流产或异常胎盘的发展，这可能会导致怀孕后期的问题。通过使用辅助生殖技术（例如体外受精），人类和牛的免疫介导的流产和胎盘不足的发生率大大增加。在这项研究中，通常具有高三个月自发流产的率很高的牛体细胞核转移妊娠将用于研究概念与母体免疫系统之间如何在体外操纵胚胎时如何破裂。

项目成果

Genetic and epigenetic regulation of major histocompatibility complex class I gene expression in bovine trophoblast cells.

• DOI: 10.1111/aji.12779
• 发表时间: 2018-01
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Shi B;Thomas AJ;Benninghoff AD;Sessions BR;Meng Q;Parasar P;Rutigliano HM;White KL;Davies CJ
• 通讯作者: Davies CJ

Trophoblast Major Histocompatibility Complex Class I Expression Is Associated with Immune-Mediated Rejection of Bovine Fetuses Produced by Cloning.

• DOI: 10.1095/biolreprod.115.136523
• 发表时间: 2016-08
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Rutigliano HM;Thomas AJ;Wilhelm A;Sessions BR;Hicks BA;Schlafer DH;White KL;Davies CJ
• 通讯作者: Davies CJ

Increased expression of pro-inflammatory cytokines at the fetal-maternal interface in bovine pregnancies produced by cloning.

• DOI: 10.1111/aji.13520
• 发表时间: 2022-03
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)