Maternal microchimerism transfers cellular immunity to offspring

母体微嵌合现象将细胞免疫传递给后代

• 批准号: 10012754
• 负责人: John J. Erickson
• 金额: $ 7.64万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012754
• 关键词: Address; Adult; Affect; Antibodies; Area; Attenuated; Bacteria; Basic Science; Biological; Bone Marrow; Breast Feeding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candida; Candida albicans; Cells; Cellular Immunity; Characteristics; Childhood; Communicable Diseases; Development; Doctor of Philosophy; Epitopes; Fellowship; Female; Fetal Development; Fetus; Fostering; Generations; Goals; Grant; Half-Life; High-Risk Pregnancy; Host Defense; Human; Human Milk; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunologics; Immunology; Immunosuppression; Individual; Infection; Influenza A virus; Institution; Investigation; Knockout Mice; Knowledge; Light; Listeria; Listeria monocytogenes; Listeriosis; Major Histocompatibility Complex; Mediating; Memory; Meningitis; Microchimerism; Modeling; Mothers; Mus; Neonatal; Newborn Infant; Oral Ingestion; Partner in relationship; Pathway interactions; Pediatric Hospitals; Phenotype; Physicians; Physiological; Predisposition; Pregnancy; Pregnant Women; Premature Infant; Property; Recombinants; Reproductive Health; Reproductive Immunology; Research; Research Personnel; Role; Scientist; Sepsis; Source; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Time; Training; Translating; Virulent; adaptive immune response; adaptive immunity; aged; career development; cell type; clinical implementation; clinically relevant; clinically significant; congenic; congenital anomaly; cytotoxic CD8 T cells; experimental study; extracellular; fetal; fetus cell; high risk; improved; in utero; lymphoid organ; male; microbiota; mortality; mutant; neonatal immunity; neonatal infection; neonatal period; neonate; next generation; offspring; pathogen; pediatrician; perinatal medicine; perinatal period; placental transfer; postnatal; prenatal; preterm newborn; reproductive fitness; tool

Project Summary/Abstract Bidirectional transplacental exchange of cells between mother and fetus occurs ubiquitously during mammalian pregnancy. Breastfeeding allows further transfer of cells from mother to offspring. The long-term persistence of these genetically foreign cells results in microchimerism. Aside from reproductive fitness, little is known about the function of maternal microchimeric cells. Given the rapid physiological changes occurring during the perinatal period, these cells have the potential to alter the developmental trajectory of progeny. Maternal microchimeric cells traffic to the bone marrow and lymphoid organs in the developing fetus. Thus, these cells have the potential to provide protection against neonatal infection and aid in maturation of the immune system. Neonates are at high risk of developing sepsis or other serious infections, and infection alone accounts for ~35% of all mortality in the neonatal period. We have established tools with which to study microchimerism, especially as it relates to the development of the fetal immune system. Further knowledge is needed regarding neonatal immunity and how it may be shaped by the maternal immune system. Our overall hypothesis is that maternal microchimeric cells provide a means of vertically transferring adaptive cellular immunity from mother to offspring. To address this key unanswered area in development and immunology, we will utilize the clinically relevant pathogens Listeria monocytogenes, which causes serious infections in pregnant mothers as well as sepsis and meningitis in neonates, and Candida albicans, which causes fungal sepsis in premature neonates. We will interrogate how the transfer from mother to fetus of cellular immune responses directed against Listeria or Candida affect susceptibility to neonatal infection. We will further characterize the phenotype of these cells and their mechanism of transfer. The results of these studies could be directly translated to therapies aimed at boosting preconceptual and postnatal cellular immunity. This would be particularly helpful in high risk pregnancies to provide protection against infection in premature infants or those with congenital anomalies. The fellowship training plan will take place under the guidance of the sponsor, Sing Sing Way, M.D/Ph.D., an infectious disease pediatrician and established physician-scientist in the areas of reproductive immunology and prenatal infection. In turn, Cincinnati Children’s Hospital is a superb institution for the study of immunology and reproductive health with a proven track record of translational and clinical implementation of basic research discoveries. The primary investigator is a pediatric physician-scientist performing fellowship training in the Department of Neonatal-Perinatal Medicine. This focused three-year grant will serve to bolster his training as a physician-scientist by providing support for dedicated research time and career development.

项目概要/摘要 母体和胎儿之间的双向经胎盘细胞交换在哺乳动物的一生中普遍存在 怀孕。母乳喂养可以将细胞从母亲进一步转移到后代。长期的坚持 这些遗传外源细胞导致微嵌合。除了生殖健康之外，人们对它知之甚少。 母体微嵌合细胞的功能。鉴于在此期间发生的快速生理变化 在围产期，这些细胞有可能改变后代的发育轨迹。产妇 微嵌合细胞在发育中的胎儿中运输至骨髓和淋巴器官。因此，这些细胞 有潜力提供针对新生儿感染的保护并有助于免疫系统的成熟。 新生儿患败血症或其他严重感染的风险很高，仅感染就可以解释 新生儿期死亡率约占所有死亡率的 35%。我们已经建立了研究微嵌合现象的工具， 特别是因为它与胎儿免疫系统的发育有关。需要进一步了解以下方面 新生儿免疫力以及母体免疫系统如何塑造新生儿免疫力。我们的总体假设是 母体微嵌合细胞提供了一种从母体垂直转移适应性细胞免疫的方法 给后代。为了解决发育和免疫学中这一关键的未解答领域，我们将利用临床 相关病原体 单核细胞增生李斯特氏菌，会导致孕妇以及孕妇严重感染 新生儿败血症和脑膜炎，以及导致早产儿真菌败血症的白色念珠菌。 我们将探讨针对李斯特菌的细胞免疫反应如何从母亲转移到胎儿 或念珠菌影响新生儿感染的易感性。我们将进一步表征这些细胞的表型 及其转移机制。这些研究的结果可以直接转化为针对以下疾病的治疗方法： 增强孕前和产后细胞免疫力。这对于高风险的情况特别有帮助 怀孕以防止早产儿或先天异常婴儿感染。 奖学金培训计划将在赞助商 Sing Sing Way 医学博士/博士 (Sing Sing Way) 的指导下进行。 传染病儿科医生和生殖免疫学领域的知名医师科学家 产前感染。反过来，辛辛那提儿童医院是免疫学和免疫学研究的一流机构。 生殖健康，在基础研究的转化和临床实施方面拥有良好的记录 发现。主要研究者是一名儿科医师兼科学家，在该领域进行进修培训 新生儿围产期医学系。这笔为期三年的重点资助将有助于加强他作为一名 通过为专门的研究时间和职业发展提供支持，成为医生科学家。