Placental extracellular vesicles as regulators of maternal adaptive immunity

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 公告RFA-AI-18-023标题为“母胎界面的免疫机制（R 01）” 怀孕构成了一个“免疫悖论”，首先由Medawar描述，尽管有能力 半同种异体胎儿可避免母体免疫排斥反应。这个悖论是 在供体卵母细胞或代孕妊娠的完全同种异体移植胎儿中加重。监管机制 在母胎界面起作用，避免母体对胎儿的免疫攻击， 保持对病原体的有效防御，在很大程度上仍然未知。我们的研究计划将 研究胎儿胎盘细胞外囊泡（EV）在调节信号与胎盘细胞的通讯中的作用。 母体适应性免疫细胞尽管已经提出在母体血液中释放的胎盘EV是一种 潜在的机制，据我们所知，这种可能性还没有在体内研究。 越来越多的证据表明，EV（例如外来体、微泡）的转移构成了一种新的生物学机制。 细胞与细胞之间的通讯机制，抗原（Ag），免疫调节介质，mRNA， 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 供体来源的EV在血液或淋巴中传播以影响次级淋巴组织中的免疫细胞 （SLT）的收件人。类似于移植，母体同种异体反应性T细胞开始意识到（非自身） SLTs中的胎儿Ag。将Ag递送至母体淋巴组织的机制可以是： 以促耐受性方式被同种异体反应性T细胞识别的免疫应答仍然未知。有趣的是，我们的初步 研究表明，与移植类似，母体白细胞（包括Ag呈递细胞）捕获 孕体来源的抗原通过无细胞介导的机制与获得EV相容。 因此，我们假设胎盘来源的EV携带父亲的Ag和免疫调节介质， 控制母体对胎儿的适应性免疫反应。我们将测试我们的假设， 分析胎盘EV在调节小鼠母体对胎儿-胎盘Ag的免疫应答中的作用 并通过研究来自正常和病理性人类妊娠的胎盘EV对母体的影响， 对胎儿-胎盘抗原的免疫应答从长远来看，我们将建立在知识和工具， 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， 正常妊娠和出现不良结局的妊娠并设计新型治疗方法 人类妊娠中免疫失衡的方法。

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.