Mechanism and function of transplacental IgD

经胎盘IgD的机制和功能

• 批准号: 10655439
• 负责人: Kang Chen
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655439
• 关键词: 1 year old; Adhesions; Adoptive Immunotherapy; Adult; Affect; Allergens; Allergic; Anaphylaxis; Anti-Allergic Agents; Antibodies; Apical; Basophils; Binding; Biochemical; Birth; Blood; Blood specimen; CD44 gene; Cattle; Cell Culture Techniques; Cell Line; Child; Child Health; Circulation; Clinical; Cues; Data; Diphtheria-Tetanus-acellular Pertussis Vaccines; Disease; Economic Burden; Education; Environment; Equilibrium; Exhibits; Fc Receptor; Female; Fetus; Food; Food Hypersensitivity; Galactose Binding Lectin; Health; Human; Hypersensitivity; IgE; Imaging Techniques; Immune; Immune signaling; Immunize; Immunoglobulin D; Immunoglobulin G; Immunologics; In Vitro; Incidence; Industrialization; Infant; Infection; Life; Mediating; Microbe; Milk; Morbidity - disease rate; Mothers; Mucous Membrane; Mus; Nature; Neonatal; Newborn Infant; Partner in relationship; Perinatal; Physiological; Placenta; Predisposition; Pregnancy; Pregnancy Complications; Production; Public Health; Reporting; Respiratory Mucosa; Respiratory Tract Infections; Retroviridae; Role; Severities; Sorting; Specimen; Sterility; Surface; Umbilical Cord Blood; United States National Institutes of Health; Vaccine Design; Vaccine Production; Vaccines; Villous; allergic response; antimicrobial; desensitization; design; effective therapy; egg; fetal; food allergen; health goals; imaging modality; immune function; improved; in utero; in vivo; infant morbidity; innovation; interest; male; maternal vaccination; mouse model; neonatal Fc receptor; neonatal health; neonatal immune system; neonatal mice; neonatal morbidity; neonate; novel; oral immunotherapy; pathogen; peripheral blood; placental transfer; prevent; prophylactic; pup; respiratory; response; small hairpin RNA; social; trans-Golgi Network; transcytosis; trophoblast; vaccine immunotherapy

Project Summary Allergies are becoming a major cause of neonatal morbidity, with food allergies showing increased incidences and significantly affecting young infants, some of which can be serious or fatal, and are associated with long- term morbidity, imposing heavy social and economic burdens. For neonatal food allergy, no effective treatment is currently available except avoiding or replacing the offending food, which is often impossible due to the ubiquitous nature of some food components. Hence, there is a critical need to identify effective means of strengthening the immune function of neonates to improve their immediate and long-term health. Human respiratory mucosa and blood harbor secreted immunoglobulin D (IgD). We found that IgD is important in respiratory immune defense by inhibiting mucosal adhesion of pathogens and activating antimicrobial and immune-amplifying functions of basophils. IgD activation of basophils also suppresses IgE-induced allergic functions, and increased food allergen-specific IgD production correlates with protection against food allergy after oral immunotherapy in children. Maternal tetanus, diphtheria, and acellular pertussis (TDaP) vaccine and food exposure in pregnancy induces the production of vaccine- and food-specific IgD that is transferred across the placenta to the fetus in humans and mice. The objectives here are to understand the mechanisms of the placental transfer of IgD and to determine if maternal IgD promotes neonatal immune protection against food allergy. We hypothesize that maternal IgD specific to vaccines or food acts as a specific and prophylactic fetal immune education cue to protect neonates against food allergy. Of note, the basophil-activating and anti- allergic functions are unique to IgD and not possessed by IgG. Employing biochemical and imaging techniques in cell culture, human placenta specimens and mouse models, studies in Aim 1 will mechanistically elucidate the placental transfer of maternal IgD. Aim 2 will determine the function of maternal food-specific IgD in the protection against IgE-mediated neonatal food allergy by integrating neonatal mouse models of IgE-mediated food-induced anaphylaxis with human cord or peripheral blood specimens of newborn babies with or without food allergy in the first year of life. Our study is expected to reveal the unique functions of maternal IgD, an ancient yet still mysterious antibody, in neonatal immune function that maternal IgG does not have, but also have a profound impact on improving neonatal health by directing the design of IgD-targeting maternal vaccines or adoptive immunotherapies.

项目摘要 过敏已成为新生儿发病率的主要原因，食物过敏显示出增加的发生率 并显着影响年轻婴儿，其中一些可能是严重或致命的，并且与长期有关 术语发病率，施加沉重的社会和经济负担。对于新生儿食物过敏，没有有效的治疗 目前可用，除了避免或替换违规食物，这通常是不可能的 某些食物成分的无处不在。因此，迫切需要确定有效的手段 增强新生儿的免疫功能，以改善其直接和长期健康。人类 呼吸道粘膜和血港分泌的免疫球蛋白D（IGD）。我们发现IgD在 通过抑制病原体的粘膜粘附并激活抗菌剂和 嗜碱性粒细胞的免疫扩增功能。嗜碱性粒细胞的IgD激活也抑制了IgE诱导的过敏反应 功能和增加的食物过敏原特异性IGD生产与防止食物过敏的保护相关 儿童口服免疫疗法后。母体破伤风，白喉和细胞百日咳（TDAP）疫苗和 怀孕的食物暴露会诱导疫苗和食物特异性IgD的产生 人类和小鼠胎儿的胎盘。这里的目标是了解 IgD的胎盘转移并确定母体IGD是否促进了针对食物的新生儿免疫保护 过敏。我们假设特定于疫苗或食物的母体IgD充当特定的预防性胎儿 免疫教育提示可保护新生儿免受食物过敏。值得注意的是，嗜碱性粒细胞激活和抗 过敏功能是IgD独有的，而IgG不具有。采用生化和成像技术 在细胞培养物，人胎盘标本和小鼠模型中，AIM 1的研究将机械阐明 母体IgD的胎盘转移。 AIM 2将确定母体食品特异性IgD在 通过整合IgE介导的新生小鼠模型来保护IgE介导的新生儿食物过敏 食物诱导的过敏反应与有或没有的新生婴儿的人绳或外周血标本 食物过敏在生命的第一年。我们的研究预计将揭示母体IgD的独特功能，这是 古代但仍然神秘的抗体，在孕妇IgG没有的新生儿免疫功能中 通过指导针对IGD靶向母体的设计，对改善新生儿健康产生深远的影响 疫苗或收养免疫疗法。