Placental extracellular vesicles as regulators of maternal adaptive immunity

RFA-AI-18-023。我们提交这份申请是为了回应最近NIAID和NICHD的资助机会 公告RFA-AI-18-023，题为“母胎界面的免疫机制(R01)” 怀孕构成了一种“免疫学悖论”，最先由Medawar描述，尽管有能力 母体免疫系统，半异基因胎儿避免母体免疫排斥。这一悖论是 在供体卵母细胞或代孕的完全同种异体移植胎儿中加重。监管机制 在母胎交界处工作，避免母体免疫攻击胎儿 保持对病原体的有效防御，在很大程度上仍然是未知的。我们提议的研究将 研究胎盘细胞外小泡(EVS)在调节信号传递中的作用 母体适应性免疫细胞。尽管在母体血液中释放的胎盘电动汽车被认为是一种 可能的机制，据我们所知，这种可能性还没有在体内进行研究。 越来越多的证据表明，EV的转移(如外周小体、微囊)构成了 一种细胞间的通讯机制，通过这种机制，抗原(AGs)、免疫调节介质、mRNAs和 非编码RNA在供体细胞和受体细胞之间水平转移。此机制类似于 EV介导的供体移植后同种异体AGS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，影响次级淋巴组织中的免疫细胞 (SLT)。类似于移植，母亲的同种异体反应性T细胞开始意识到(非自我) SLT中的胎儿AGS。递送到母亲淋巴组织的AGS的机制可以是 由同种异体反应性T细胞识别的促耐受方式仍不清楚。有趣的是，我们的初选 研究表明，类似于移植，母体白细胞(包括抗原提呈细胞)被捕获 母体SLT中概念衍生的AGS通过一种与EVS获得相容的无细胞介导机制。 因此，我们假设胎盘来源的电动汽车携带父亲的ags和免疫调节介质。 来控制母体对胎儿的适应性免疫反应。我们将通过以下方式验证我们的假设 胎盘EVS在小鼠胎盘AGS免疫应答中的作用分析 并通过研究来自正常和病理人类妊娠的胎盘EV对母体的影响 对胎盘抗原的免疫应答。从长远来看，我们将建立在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 正常妊娠和合并不良结局的妊娠并设计新的治疗方法 人类妊娠期免疫失衡的治疗方法。

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.