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。我们提交此申请是为了响应最近的 NIAID 和 NICHD 资助机会。 标题为“母胎界面的免疫机制 (R01)”的公告 RFA-AI-18-023 怀孕构成了一个“免疫学悖论”，首先由 Medawar 描述，尽管有能力 母体免疫系统，半同种异体胎儿避免了母体免疫排斥。 在供体卵母细胞或代孕妊娠的完全同种异体移植胎儿中强调调节机制。 在母体-胎儿界面运行，避免母体对胎儿的免疫攻击，同时 保持对病原体的有效防御，在很大程度上仍然未知。 研究胎儿胎盘细胞外囊泡 (EV) 在向胎儿传递调节信号中的作用 尽管母体血液中释放的胎盘 EV 已被提议作为一种母体适应性免疫细胞。 潜在机制，据我们所知，这种可能性尚未在体内进行研究。 越来越多的证据表明，EV 的转移（例如外泌体、微泡）构成了 细胞间通讯的机制，通过抗原（Ag）、免疫调节介质、mRNA 和 非编码 RNA 在供体细胞和受体细胞之间水平转移。 移植后 EV 介导的供体同种异体 Ag 和免疫刺激介质的释放。 供体来源的 EV 在血液或淋巴液中传播，影响次级淋巴组织中的免疫细胞 与移植类似，母体同种异体反应性 T 细胞会意识到（非自身）。 SLT 中的胎儿 Ag 传递至母亲淋巴组织的机制。 被同种异体反应性 T 细胞以促耐受方式识别的情况仍然未知。 研究表明，与移植类似，母体白细胞（包括抗原呈递细胞）捕获 通过与获得 EV 相容的无细胞介导机制，在母体 SLT 中产生源自孕体的 Ag。 因此，我们认为胎盘来源的 EV 携带父本 Ag 和免疫调节介质 控制母体针对胎儿的适应性免疫反应 我们将通过以下方式检验我们的假设。 分析胎盘 EV 在调节小鼠母体对胎儿胎盘 Ag 的免疫反应中的作用 并通过研究正常和病理人类妊娠的胎盘 EV 对母体的影响 对胎儿胎盘抗原的免疫反应 从长远来看，我们将建立在已开发的知识和工具的基础上。 在移植免疫学中机械地定义免疫能力和耐受性之间的平衡 正常妊娠和并发不良后果的妊娠并设计新的治疗方法 人类怀孕期间免疫失衡的方法。