STUDIES OF MATERNAL AND NEONATAL IMMUNITY

母亲和新生儿免疫力的研究

• 批准号: 6543262
• 负责人: THOMAS B TOMASI
• 金额: $ 37.43万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6543262
• 关键词: DNA footprinting; MHC class II antigen; clinical research; gel mobility shift assay; gene expression; gene induction /repression; gene mutation; genetic promoter element; genetic regulatory element; genetic transcription; genetically modified animals; histocompatibility antigens; human tissue; immunogenetics; immunoprecipitation; immunoregulation; laboratory mouse; laboratory rat; pregnancy immunology; tissue /cell culture; transcription factor; transfection; trophoblast

DESCRIPTION (provided by applicant): The failure of the trophoblast to express MHC antigens is believed to be essential for survival of the fetus during pregnancy. It is therefore likely that strong evolutionary pressures to preserve reproduction would develop tight overlapping regulatory controls of these genes. We have shown that in trophoblasts, class II expression is mediated by at least two control mechanisms involving repression of class II transactivator transcription and an upstream negative regulatory element [NRE]. Fusion of B cells expressing class II with trophoblast cells has been reported to result in silencing of the CIITA gene in the heterokaryon suggesting a repressor in the trophoblast. Repression of class II in trophoblast cells has been postulated to result from several candidate inhibitors of CIITA transcription [Blimp-1, TGF-beta]. We have demonstrated that low concentrations of deacetylase inhibitors [DAIs] activate class II and costimulatory molecules on trophoblast cells without demonstrable CIITA. DAIs at higher concentrations induce cell cycle blocks and apoptotic cells expressing class II, CD4O, CD8O and CD86. This grant will explore the possibility of a CIITA independent pathway of class II activation mediated by epigenetic agents, such as acetylation and methylation, in trophoblast cells and attempt to further define the underlying molecular pathways. The physiological relevance of these findings to the ability of the fetal trophoblast cells to initiate an immune response will be investigated. The expression of MHC and other key immune genes will be evaluated on apoptotic trophoblast cells produced by DAIs and similar other toxic agents and on exosome derived trophoblast cell lines and on fresh murine trophoblast cells. Hopefully, these studies will enhance our understanding of the general mechanisms that regulate class II expression and certain other immune genes on trophoblast cells. This work may also have application to areas of clinical relevance, such as abortion, autoimmunity and cancer.

描述（由申请人提供）：滋养层不能表达MHC抗原被认为是妊娠期间胎儿存活所必需的。因此，很可能是强大的进化压力，以保持生殖将开发这些基因的严格重叠的监管控制。我们已经表明，在滋养层，II类表达介导的至少两个控制机制，涉及抑制II类反式激活因子转录和上游负调控元件[NRE]。据报道，表达II类的B细胞与滋养层细胞的融合导致异核体中CIITA基因的沉默，表明滋养层中存在阻遏物。已经假定滋养层细胞中II类的抑制由CIITA转录的几种候选抑制剂[Blimp-1，TGF-β]引起。我们已经证明，低浓度的去乙酰化酶抑制剂（DAI）激活滋养层细胞上的II类和共刺激分子，而没有明显的CIITA。较高浓度的DAI诱导细胞周期阻滞和表达II类、CD 4 O、CD 8 O和CD 86的凋亡细胞。这项资助将探索由表观遗传因子介导的第二类激活的CIITA独立途径的可能性，如在滋养层细胞中的乙酰化和甲基化，并试图进一步确定潜在的分子途径。将研究这些发现与胎儿滋养层细胞启动免疫应答能力的生理相关性。将在由DAI和类似的其他毒性剂产生的凋亡滋养层细胞上以及在外来体衍生的滋养层细胞系上和在新鲜的鼠滋养层细胞上评价MHC和其他关键免疫基因的表达。希望这些研究将增强我们对滋养层细胞上调节II类表达和某些其他免疫基因的一般机制的理解。这项工作也可能适用于临床相关领域，如堕胎，自身免疫和癌症。