Mechanism and function of transplacental IgD

经胎盘IgD的机制和功能

• 批准号: 10448491
• 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/10448491
• 关键词: 1 year old; Adhesions; Adoptive Immunotherapy; Adult; Affect; Allergens; Allergic; Allergy to eggs; Anaphylaxis; Anti-Allergic Agents; Antibodies; Apical; Basophils; Binding; Biochemical; Birth; Blood; Blood Circulation; Blood specimen; CD44 gene; Cattle; Cell Culture Techniques; Cell Line; Child; Child Health; Clinical; Cues; Data; Diphtheria; Disease; Economic Burden; Education; Environment; Equilibrium; Exhibits; Fc Receptor; Female; Fetus; Food; Food Hypersensitivity; Galactose Binding Lectin; Government; Health; Human; Hypersensitivity; IgE; Imaging Techniques; Immune; Immune signaling; 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; Pertussis Vaccine; Physiological; Placenta; Pregnancy; Pregnancy Complications; Production; Public Health; Reporting; Respiratory Mucosa; Respiratory Tract Infections; Retroviridae; Role; Severities; Specimen; Sterility; Surface; Tetanus; Umbilical Cord Blood; United States National Institutes of Health; Vaccine Design; Vaccine Production; Vaccines; Villous; allergic response; antimicrobial; base; desensitization; design; effective therapy; egg; fetal; food allergen; health goals; imaging modality; immune function; immune imaging; 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 过敏症正在成为新生儿发病的主要原因，食物过敏的发病率有所增加 并严重影响幼儿，其中一些可能是严重或致命的，并与长期- 长期发病率，造成沉重的社会和经济负担。对于新生儿食物过敏，尚无有效治疗方法 目前除了避免或更换违规食品外，这通常是不可能的，因为 一些食物成分的普遍存在的性质。因此，迫切需要确定有效的手段， 加强新生儿的免疫功能，以改善其近期和长期健康。人类 呼吸道粘膜和血液含有分泌的免疫球蛋白D（IgD）。我们发现IgD在 呼吸道免疫防御通过抑制病原体的粘膜粘附和激活抗微生物和 嗜碱性粒细胞的免疫放大功能。IgD激活嗜碱性粒细胞也抑制IgE诱导的过敏性 食物过敏原特异性IgD产生增加与食物过敏保护相关 儿童口服免疫治疗后。产妇破伤风、白喉和无细胞百日咳疫苗， 妊娠期食物暴露诱导疫苗和食物特异性IgD的产生， 人类和老鼠的胎盘。这里的目标是了解 胎盘转移IgD，并确定母体IgD是否促进新生儿对食物的免疫保护 过敏我们假设，母体对疫苗或食物特异性的IgD作为特异性的和预防性的胎儿免疫球蛋白， 免疫教育提示保护新生儿免受食物过敏。值得注意的是，嗜碱性粒细胞活化和抗- 过敏性功能是IgD所特有的，而不是IgG所具有的。利用生物化学和成像技术 在细胞培养、人胎盘标本和小鼠模型中，目标1中的研究将从机理上阐明 母体IgD的胎盘转移。目的2将确定母体食物特异性IgD在妊娠中的作用。 通过整合IgE介导的新生小鼠模型对IgE介导的新生儿食物过敏的保护作用 新生儿脐带血或外周血标本食物诱导的过敏反应， 食物过敏在生命的第一年。我们的研究有望揭示母体IgD的独特功能， 古老而神秘的抗体，在新生儿免疫功能，母亲的IgG没有，但也 通过指导IgD靶向孕产妇免疫球蛋白的设计， 疫苗或过继性免疫疗法。