Placental extracellular vesicles as regulators of maternal adaptive immunity

胎盘细胞外囊泡作为母体适应性免疫的调节剂

• 批准号: 9797467
• 负责人: Adrian E. Morelli
• 金额: $ 54.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797467
• 关键词: Address; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; Awareness; Biology; Blood; Cell Communication; Cell physiology; Cells; Chronic; Communication; Competence; Conceptus; Decidua; Dendritic Cells; Disease; Embryo; Equilibrium; Fetus; Funding Opportunities; Graft Rejection; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunocompetence; Immunologics; Immunology; Immunology procedure; Inflammatory; Investigation; Knowledge; Leukocytes; Lymph; Lymphoid; Lymphoid Tissue; Maintenance; Maternal-Fetal Exchange; Mediating; Mediator of activation protein; Messenger RNA; Mothers; Mus; National Institute of Allergy and Infectious Disease; National Institute of Child Health and Human Development; Natural Immunity; Oocytes; Organ; Outcome; Pathogenesis; Pathologic; Pathway interactions; Placenta; Placenta Diseases; Play; Pre-Eclampsia; Pregnancy; Premature Birth; Regulation; Research; Role; Signal Transduction; System; T cell response; T-Lymphocyte; Testing; Tissues; Transfer RNA; Transplantation; Travel; Untranslated RNA; adaptive immune response; adaptive immunity; adverse outcome; allograft rejection; base; embryo/fetus antigen; embryonic antigen; exosome; extracellular vesicles; fetal; humanized mouse; immunoregulation; in vivo; microvesicles; mouse model; multiphoton microscopy; novel therapeutic intervention; pathogen; pregnancy disorder; pregnancy immunology; prevent; response; skills; tool; translational model; vesicular release

RFA-AI-18-023. We submit this application in response to the recent NIAID and NICHD Funding Opportunity Announcement RFA-AI-18-023 titled “Immune mechanisms at the maternal-fetal interface (R01)” Pregnancy constitutes an “immunological paradox”, first described by Medawar, where despite the competent maternal immune system, the semi-allogeneic fetus avoids maternal immune rejection. This paradox is accentuated in the fully allograft fetus in donor oocytes or surrogate pregnancies. The regulatory mechanisms that operate at the maternal-fetal interface that avoid the maternal immunologic attack to the fetus while maintaining competent defense against pathogens, remain largely unknown. Our proposed research will investigate the role of feto-placental extracellular vesicles (EVs), in communication of regulatory signals to the maternal adaptive immune cells. Although placental EVs released in maternal blood has been proposed as a potential mechanism, to our knowledge, such possibility has not been investigated in vivo. There is increasing evidence that transfer of EVs (e.g. exosomes, microvesicles), constitutes a mechanism of cell-to-cell communication by which antigens (Ags), immuno-regulatory mediators, mRNAs, and non-coding RNAs are transferred horizontally between donor and acceptor cells. This mechanism resembles the EV-mediated release of donor allogeneic Ags and immuno-stimulatory mediators after transplantation. These donor-derived EVs travel in the blood or lymph to influence immune cells in the secondary lymphoid tissues (SLTs) of the recipient. Akin to transplantation, maternal allo-reactive T cells become aware of the (non-self) fetal Ags in SLTs. The mechanisms by which Ags that are delivered to the mother’s lymphoid tissues can be recognized by the allo-reactive T cells in a pro-tolerogenic fashion remain unknown. Interestingly, our preliminary studies indicate that, analogous to transplantation, maternal leukocytes (including Ag-presenting cells) capture conceptus-derived Ags in maternal SLTs via a cell-free mediated mechanism compatible with acquisition of EVs. Thus, we hypothesize that placenta-derived EVs carry paternal Ags and immuno-regulatory mediators that control the maternal adaptive immune response against the fetus. We will test our hypothesis by analyzing the role of placental EVs in regulation of the mouse maternal immune response to feto-placental Ags and by investigating the effect of placental EVs from normal and pathological human pregnancies on the maternal immune response to feto-placental Ags. Long-term, we will build on knowledge and tools that were developed in transplant immunology to mechanistically define the balance between immune competence and tolerance in normal pregnancies and in pregnancies complicated by adverse outcomes and devise novel therapeutic approaches to immunological imbalance in human pregnancy.

RFA-AI-18-023。我们根据最近的NIAID和NICHD资助机会提交此申请 公告RFA-AI-18-023标题为“ Mater-Fetal界面（R01）的免疫机制” 怀孕构成了Medawar最初描述的“免疫悖论”，目的地是胜任的 孕产妇免疫系统，半合成性胎儿避免了母体免疫排斥。这个悖论是 在供体卵母细胞或替代妊娠的完全同种同类胎儿中突出。监管机制 在孕产妇界面上运行，避免了母体免疫攻击胎儿 维持对病原体的有能力的防御，在很大程度上尚不清楚。我们提出的研究将 研究胎儿细胞外蔬菜（EV）的作用，在调节信号与 孕产妇自适应免疫小球。尽管已经提出了在母体血液中释放的斑点电动汽车 据我们所知，潜在的机制尚未在体内研究。 有越来越多的证据表明，电动汽车的转移（例如外泌体，微测中）构成了 抗原（AGS），免疫调节介质，mRNA和 非编码RNA在供体和受体细胞之间水平转移。这种机制类似于 移植后EV介导的供体同种异体AG和免疫刺激介质的释放。这些 供体衍生的电动汽车以血液或淋巴传播，以影响继发性淋巴组织中的免疫细胞 （slts）收件人。类似于移植，母体同种反应性T细胞意识到（非自我） SLT中的胎儿AG。传递到母亲淋巴组织的AG的机制可以是 在亲染色的方式中，被同种反应性T细胞识别是未知的。有趣的是，我们的初步 研究表明，类似于移植，母体白细胞（包括呈递Ag的细胞）捕获 孕产妇SLT中的概念源性AG通过与电动汽车的获取兼容的无细胞介导机制。 这是我们假设，派生的EV携带父亲AG和免疫调节介质 控制孕产妇适应性免疫反应针对胎儿。我们将通过 分析位置EV在调节小鼠对胎儿ags的遗产免疫响应中的作用 并通过调查正常和病态人类怀孕对母亲的胎盘电动汽车的影响 对胎儿AG的免疫反应。长期，我们将基于开发的知识和工具 在移植免疫学中，机械定义免疫能力和公差之间的平衡 正常怀孕和在怀孕中因不良结果而复杂并设计出新的治疗 人类怀孕中免疫失衡的方法。