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NIAID和NICHD的资助机会