PASSIVE IMMUNIZATION FOR DEFINING FUNCTION OF PLACENTAL MHC CLASS I MOLECULES

用于定义胎盘 MHC I 类分子功能的被动免疫

• 批准号: 7716460
• 负责人: THADDEUS G GOLOS
• 金额: $ 8.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-23 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716460
• 关键词: Aftercare; Angiogenic Factor; Animals; CD209 gene; CD8B1 gene; Cells; Class; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Decidua; Development; Endometrial; Endometrial Stromal Cell; Endometrium; Environment; Evaluation; FCGR3B gene; Flow Cytometry; Funding; Grant; Growth; HLA G antigen; Health Services Research; Histocompatibility Antigens Class I; Human; Incomplete spontaneous abortion; Institution; Leukocytes; MHC Class I Genes; Macaca mulatta; Maternal-Fetal Exchange; Modeling; Monitor; Mus; NCAM1 gene; Natural Killer Cells; Numbers; Passive Immunization; Patient currently pregnant; Peripheral; Play; Population; Pregnancy; Pregnancy Outcome; Pregnancy loss; Primates; Research; Research Personnel; Resources; Role; Services; Site; Source; T-Lymphocyte; Thinking; United States National Institutes of Health; abortion; cytokine; day; implantation; macrophage; monocyte; nonhuman primate; peripheral blood; response; success; trafficking; trophoblast

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To identify the function of MHC class I expression and endometrial NK cells at the maternal-fetal interface. During human and non-human primate pregnancy, the uterine endometrium differentiates into the decidua. Decidual NK cells are believed to play a key role in the development of a proper environment for placental growth by producing cytokines and angiogenic factors in response to nonclassical MHC class I molecules on the placental trophoblasts. These include HLA-G in human and Mamu-AG in the rhesus monkey. The majority of rhesus decidual NK cells are CD56+ cells, co-expressing CD16 and CD8. Anti-CD16 (3G8) mouse mAb and anti-CD8 (cM-T807) human-mouse chimeric mAb were used in non-pregnant and pregnant animals at day 18 of gestation. The efficiency of depletion was monitored by flow cytometry and animals were euthanized 7 days after treatment. The administration of anti-CD16 resulted in 62-87% depletion of peripheral blood NK cells; anti-CD8 treatment depleted 96-99% of peripheral blood NK cells, as well as peripheral blood CD8+ T cells. Immunohistochemical (IHC) evaluation of the endometrium in two anti-CD16 treated non-pregnant animals revealed minimal effect on the endometrium in one animal, and a substantial decrease of NK cells and reduced differentiation of endometrial stromal cells in a second animal. The NK cell depletion in pregnant animals was associated with complete abortion in one animal (anti-CD8-treatment) and threatened/incomplete abortion in other animals. IHC examination of the decidua in treated pregnant animals revealed reduced NK cells and macrophages, and increased T cells in all animals (three anti-CD8 and one anti-CD16 treatments). The extent of decidual NK cell depletion mirrored the outcome of pregnancy. Compared with the untreated control group decidual NK cell depletion was more severe in animal with complete abortion than in animals with threatened/incomplete abortion. Analogous decreases were seen with CD68+ macrophages and DC-SIGN+ cells with the exception that the anti-CD16 treated animal had a normal number of DC-SIGN+ cells. Thus, depletion of peripheral blood NK cells was associated with altered endometrial and decidual leukocyte populations and threatened or complete pregnancy loss. Since peripheral NK cells and monocytes are thought to traffic to the implantation site in early pregnancy, their disrupted numbers in abnormal pregnancies indicates that an appropriate disposition of leukocytes may be necessary for pregnancy success in this primate model. This research used WNPRC Animal Services and Research Services.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 确定MHC I类表达和子宫内膜NK细胞的功能。 在人类和非人类灵长类动物妊娠期间，子宫子宫内膜与DECIDUA区分开。据信，deciDual NK细胞在胎盘滋养细胞上对非经典MHC I类分子的响应来响应非经典MHC I类分子而产生细胞因子和血管生成因子，在适当的胎盘生长环境的发展中起关键作用。其中包括人类的HLA-G和恒河猴中的Mamu-Ag。大多数恒河猴NK细胞是CD56+细胞，共表达CD16和CD8。在妊娠的第18天，在非怀孕和怀孕的动物中使用了抗CD16（3G8）小鼠mAb和抗CD8（CM-T807）人鼠嵌合mab。 通过流式细胞仪监测耗竭的效率，并在治疗后7天安乐死。抗CD16的给药导致周围血液NK细胞的耗竭62-87％。抗CD8处理耗尽了96-99％的外周血NK细胞以及外周血CD8+ T细胞。 对两种抗CD16治疗的非妊娠动物的子宫内膜的免疫组织化学（IHC）评估显示，一只动物对子宫内膜的影响很小，NK细胞的大幅度降低并减少了第二动物的子宫内膜细胞的分化。孕妇动物中的NK细胞耗竭与一只动物（抗CD8治疗）完全流产有关，并威胁/在其他动物中威胁/不完全流产。 IHC对经过治疗的怀孕动物中DecIDUA的检查显示，NK细胞和巨噬细胞降低，并且所有动物的T细胞增加（三种抗CD8和一种抗CD16治疗）。 NK细胞耗竭的程度反映了妊娠的结果。 与未处理的对照组NK细胞耗尽相比，完全流产的动物比受到威胁/不完全流产的动物更为严重。与CD68+巨噬细胞和DC-SIGN+细胞一起观察到类似的减少，但抗CD16治疗的动物具有正常数量的DC-SIGN+细胞。因此，外周血NK细胞的耗竭与子宫内膜和决结白细胞种群的改变有关，并威胁或完全妊娠丧失。由于外周NK细胞和单核细胞在怀孕初期被认为是植入部位的流动，因此它们在异常怀孕中的数量破坏表明，在这种灵长类动物模型中，妊娠成功可能是必要的。这项研究使用了WNPRC动物服务和研究服务。