Mechanism and function of transplacental IgD

经胎盘IgD的机制和功能

基本信息

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
项目类别：
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

项目摘要

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.

项目概要过敏正在成为新生儿发病的一个主要原因，食物过敏的发病率有所增加并严重影响年幼的婴儿，其中一些可能是严重的或致命的，并且与长期长期发病，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有问题的食物外，这通常是不可能的，因为某些食品成分的普遍存在性。因此，迫切需要找到有效的手段增强新生儿的免疫功能，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 在以下方面很重要通过抑制病原体粘膜粘附并激活抗菌剂和活性剂来实现呼吸道免疫防御嗜碱性粒细胞的免疫增强功能。嗜碱性粒细胞的 IgD 激活也可抑制 IgE 诱导的过敏功能，并且增加食物过敏原特异性 IgD 的产生与预防食物过敏相关儿童口服免疫治疗后。孕产妇破伤风、白喉和无细胞百日咳 (TDaP) 疫苗和怀孕期间的食物接触会诱导疫苗和食物特异性 IgD 的产生，并在体内转移人类和小鼠的胎盘到胎儿。这里的目标是了解 IgD 的胎盘转移并确定母体 IgD 是否促进新生儿对食物的免疫保护过敏。我们假设母体针对疫苗或食物的 IgD 可以作为胎儿的特异性预防性 IgD。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特有的，IgG不具备。采用生化和成像技术在细胞培养、人类胎盘标本和小鼠模型中，目标 1 中的研究将从机制上阐明母体 IgD 的胎盘转移。目标 2 将确定母体食物特异性 IgD 在通过整合 IgE 介导的新生小鼠模型来预防 IgE 介导的新生儿食物过敏人类脐带或新生儿外周血标本中食物引起的过敏反应有或没有生命第一年的食物过敏。我们的研究有望揭示母体 IgD 的独特功能，古老而又神秘的抗体，在新生儿免疫功能中是母体IgG所不具备的，但也通过指导针对 IgD 的孕产妇设计，对改善新生儿健康产生深远影响疫苗或过继免疫疗法。