FUNCTIONAL COOPERATION BETWEEN TROPHOBLAST HLA-G AND B7 FAMILY

滋养层 HLA-G 和 B7 家族之间的功能合作

• 批准号: 7699715
• 负责人: MARGARET G PETROFF
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7699715
• 关键词: Affect; Allogenic; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Biological Assay; CD80 Antigens; CD8B1 gene; Cell Line; Cells; Cessation of life; Class; Communication; Condition; Data; Equilibrium; Family; Family member; Fetus; Goals; HLA Antigens; Histamine H1 Receptors; Histological Techniques; Immune; Immune Tolerance; Immune response; Immune system; In Vitro; Infection; Infertility; Interferons; Lead; Leukocytes; Lymphocyte; Lymphocyte Activation; Malignant Neoplasms; Maternal-Fetal Exchange; Mediating; Molecular; Mothers; Mus; Oxygen; Pathogenesis; Pathologic; Pattern; Peptides; Physiological; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy loss; Premature Birth; Production; Proteins; Relative (related person); Research; Resources; Signal Transduction; Single Nucleotide Polymorphism; Surface; System; T-Lymphocyte; Techniques; Testing; Tissues; Viral; Work; abstracting; cell type; cytokine; design; fetal; fetus cell; human PDCD1LG1 protein; immune function; in vivo; insight; leukocyte activation; member; prevent; protein expression; trophoblast

ABSTRACT-PROJECT 11 Background. Stimulation of lymphocytes requires the delivery of two cooperating signals provided by antigen presenting cells. The first signal is provided by human leukocyte antigens (HLA), while the second is provided by a member of the B7 family of costimulatory molecules. Unlike classical antigen presenting cells, however, trophoblast cells possess a distinctive combination of both classes of molecules. Specifically, trophoblast cells constitutively express non-classical HLA-G molecules as well as the newly discovered B7 family member, B7- H1. In vitro and in vivo studies have shown that expression of the B7 and HLA proteins can inhibit leukocyte activation and alter cytokine secretion, and that aberrant expression of these proteins can contribute to conditions such as cancer and autoimmune disease. Our preliminary data show that trophoblast-associated Hl_A-G and B7-H1 also inhibits production of the proinflammatory cytokine interferon-y by T cells, suggesting that trophoblast cells use these molecules for protection of the fetal semiallograft. We and others have also demonstrated that oxygen and proinflammatory cytokines, which are associated with preeclampsia and preterm delivery, alter expression of trophoblast-associated B7-H1 and HLA-G. Thus, altered expression of trophoblast HLA and B7s precipitated by abnormal oxygen and/or cytokine conditions in the placenta could lead to the reduced or enhanced ability of trophoblast cells to inhibit maternal leukocytes. Specific goals. The findings of the expression of unique members of the HLA and B7 families by trophoblast cells raises the question of whether these molecules functionally cooperate to deliver signals to lymphocytes in a manner similar to classical members of these families. The Specific Aims of Project II are to 1) determine the relative levels of expression of members of HLA-G and B7-H1 in normal and pathologic pregnancies; 2) determine whether the presence of trophoblast B7-H1 influences the effects of trophoblast HLA-G on maternal T lymphocytes; 3) examine whether B7-H1 influences antigen presentation activity of HLA-G1-expressing trophoblast cell lines. In Aim 1, tissue and purified trophoblast cells from placentas of normal, preeclamptic, and preterm pregnancies will be examined by molecular, histological, and flow cytometric techniques to determine whether the balance of these proteins is offset in compromised pregnancies. In Aim 2, we will perform functional assays to compare the ability of HLA and B7 family molecules, alone and in combination, to regulate leukocyte function. Finally, Aim 3 is designed to determine whether trophoblast-associated HLA-G can provide anti-viral protection at the maternal-fetal interface. Here, we will test whether HLA-G can present viral peptides to T cells, and whether the presence of B7-H1 affects its ability to do so.

摘要-项目 11 背景。淋巴细胞的刺激需要传递由抗原提供的两个协同信号 呈现细胞。第一个信号由人类白细胞抗原 (HLA) 提供，而第二个信号由人类白细胞抗原 (HLA) 提供 由共刺激分子 B7 家族的成员产生。然而，与经典的抗原呈递细胞不同， 滋养层细胞具有两类分子的独特组合。具体而言，滋养层细胞 组成型表达非经典 HLA-G 分子以及新发现的 B7 家族成员 B7- H1。体外和体内研究表明，B7和HLA蛋白的表达可以抑制白细胞 激活并改变细胞因子分泌，并且这些蛋白质的异常表达可能导致 癌症和自身免疫性疾病等疾病。我们的初步数据表明，滋养层相关 Hl_A-G 和 B7-H1 还抑制 T 细胞产生促炎细胞因子干扰素-y，这表明 滋养层细胞利用这些分子来保护胎儿半同种异体移植物。我们和其他人也 证明氧和促炎细胞因子与先兆子痫和 早产，改变滋养层相关的 B7-H1 和 HLA-G 的表达。因此，改变表达 胎盘中异常氧和/或细胞因子条件沉淀的滋养层 HLA 和 B7 可能 导致滋养层细胞抑制母体白细胞的能力降低或增强。 具体目标。滋养层表达 HLA 和 B7 家族独特成员的发现 细胞提出了这样的问题：这些分子是否功能性地合作向淋巴细胞传递信号 与这些家族的古典成员类似的方式。项目 II 的具体目标是 1) 确定 正常和病理妊娠中 HLA-G 和 B7-H1 成员的相对表达水平； 2） 确定滋养层 B7-H1 的存在是否影响滋养层 HLA-G 对母体的影响 T淋巴细胞； 3)检查B7-H1是否影响HLA-G1表达的抗原呈递活性 滋养层细胞系。在目标 1 中，来自正常、先兆子痫、 和早产将通过分子、组织学和流式细胞术技术进行检查，以 确定这些蛋白质的平衡是否在妊娠受损时被抵消。在目标 2 中，我们将 进行功能测定来比较 HLA 和 B7 家族分子单独和组合的能力， 调节白细胞功能。最后，目标 3 旨在确定滋养层相关的 HLA-G 是否 可以在母胎界面提供抗病毒保护。在这里，我们将测试HLA-G是否可以呈现 病毒肽对 T 细胞的影响，以及 B7-H1 的存在是否会影响其这样做的能力。