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Mechanisms promoting pregnancy success: Dendritic cells as intermediators between Human Chorionic Gonadotropin and Regulatory T cells

促进妊娠成功的机制：树突状细胞作为人绒毛膜促性腺激素和调节性 T 细胞之间的中介

基本信息

批准号：
266993438
负责人：
Privatdozentin Dr. Anne Schumacher
金额：
--
依托单位：
Department Umweltimmunologie und Core Facility Studien
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/266993438?language=en
关键词：
Mechanisms promoting pregnancy success Dendritic

项目摘要

Infertility or miscarriage can no longer be considered a personal problem but rather a public health problem. The inability to conceive a child not only results in personal conflicts but has also been associated with psychiatric disorders. Beside intensive costs for infertility treatments there are further costs involved managing mental health complications. For this reason a detailed understanding of mechanisms resulting in successful pregnancies is essential. Ultimately this will advance therapeutic interventions for patients suffering infertility or miscarriages and reduce the number of women developing mental disorders due to reproductive failure. During pregnancy the maternal immune system is challenged by the presence of foreign paternal antigens expressed by the semi-allogeneic fetus. Fetal survival within the hostile maternal uterus can only be achieved by a fine regulation of maternal immune responses towards fetal alloantigens. Here, pregnancy hormones like the human Chorionic Gonadotropin (hCG) are proposed to be important immune modulators. In previous studies we showed that hCG supports fetal tolerance by enhancing the number and activity of regulatory T cells (Treg). However, it has not been clarified whether hCG influences Treg directly or via indirect pathways. Tolerogenic dendritic cells (DCs) were described as potent inducers of Treg and there is evidence that hCG may retain a tolerogenic profile of DCs. However, in vitro data describing an influence of hCG on DCs is inconsistent and in vivo data is limited. Moreover, to the best of our knowledge there are no available studies employing human samples in the literature that confirm DCs as direct intermediators between hCG and Treg during pregnancy. Thus, the overall aim of our planned research is to test the hypothesis that hCG indirectly influences Treg via regulation of DCs during human pregnancy. To achieve this we will (1) test the influence of hCG on the phenotype and functionality of human peripheral DCs, (2) evaluate the effect of different hCG isoforms on the phenotype and functionality of human peripheral DCs (3) test whether trophoblasts from patients having spontaneous abortions or normal pregnant women will differently influence human peripheral DC behavior and (4) determine whether DC modulation by trophoblasts from different pregnancy outcomes will influence Treg induction. Thereby, our proposed research will advance the state-of-the-art in the reproductive immunology field by gaining more knowledge about the basic mechanisms supporting fetal tolerance. Moreover, we strongly believe our research to have wider implications in other immune-related fields such as organ transplantation, autoimmunity and cancer. Finally, we hope that our research will build bridges between basic research and clinical application resulting in advanced therapeutic interventions for patients suffering infertility and miscarriages.

不孕不育或流产不再被视为个人问题，而是公共卫生问题。无法怀孕不仅会导致个人冲突，而且还与精神疾病有关。除了不孕症治疗的密集成本外，还有涉及管理心理健康并发症的进一步成本。因此，详细了解导致成功怀孕的机制至关重要。最终，这将促进对不孕症或流产患者的治疗干预，并减少因生殖失败而患精神疾病的妇女人数。在妊娠期间，母体免疫系统受到半同种异体胎儿表达的外源父方抗原的挑战。胎儿在母体子宫内的存活只能通过母体对胎儿同种异体抗原的免疫反应的精细调节来实现。在这里，妊娠激素如人绒毛膜促性腺激素（hCG）被认为是重要的免疫调节剂。在以前的研究中，我们发现hCG通过增加调节性T细胞（Treg）的数量和活性来支持胎儿耐受。然而，hCG是否直接或通过间接途径影响Treg尚未阐明。致耐受性树突状细胞（DC）被描述为Treg的有效诱导剂，并且有证据表明hCG可以保留DC的致耐受性特征。然而，在体外数据描述的影响，hCG对DC是不一致的，在体内的数据是有限的。此外，据我们所知，在文献中没有使用人类样本的可用研究证实DC是妊娠期间hCG和Treg之间的直接中介。因此，我们计划的研究的总体目标是检验hCG在人类妊娠期间通过调节DC间接影响Treg的假设。为了实现这一点，我们将（1）测试hCG对人外周DC的表型和功能的影响，（2）评估不同hCG同种型对人外周DC的表型和功能的影响（3）测试来自具有自然流产的患者或正常孕妇的滋养层是否将不同地影响人外周DC行为和（4）确定不同妊娠结局的滋养层细胞对DC的调节是否会影响Treg的诱导。因此，我们提出的研究将通过获得更多关于支持胎儿耐受的基本机制的知识来推进生殖免疫学领域的最新技术。此外，我们坚信我们的研究在其他免疫相关领域，如器官移植，自身免疫和癌症，具有更广泛的意义。最后，我们希望我们的研究将在基础研究和临床应用之间建立桥梁，为不孕症和流产患者提供先进的治疗干预措施。