Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants

新生儿和婴儿对过敏原反应性发展的脂质调节

基本信息

批准号：
9919537
负责人：
JOAN M COOK-MILLS
金额：
$ 48.49万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919537
关键词：
Allergens Allergic Allergic Disease Allergic inflammation Animals Anti-Inflammatory Agents Asthma Bone Marrow Cell Count Cell Differentiation process Cell physiology Clinical Research Complex Consumption Data Dendritic Cells Development Dietary Fats Dietary Supplementation Discipline of Nursing Environmental Risk Factor Female Fetal Liver Fetus Future Generations Genetic Goals Hematopoiesis High Density Lipoproteins Human Human Milk Hydrocortisone Hypersensitivity ITGAM gene ITGAX gene IgE In Vitro Infant Inflammatory Interleukin-4 Intervention Lead Life Lipids Low-Density Lipoproteins Lung Lung Inflammation Mediating Mediator of activation protein Milk Mothers Mouse Strains Mus Neonatal Placenta Plants Plasma Pregnancy Prevalence Protein Isoforms Regulation Reporting Risk Supplementation Testing Time Tocopherols Umbilical Cord Blood allergic response alpha Tocopherol atopy design fetal gamma-Tocopherol immunoregulation mother nutrition neonate novel octadecadienoic acid offspring particle pregnant response

项目摘要

In animals and humans, offspring of allergic mothers have increased responsiveness to allergen. The maternal mediators of allergic mothers that increase allergen responsiveness in the offspring are not known. We demonstrated that the fetal liver and offspring of allergic mice have increased numbers of distinct DC subsets. Transfer of splenic dendritic cells (DCs) from neonates of allergic mothers to recipient neonates from non- allergic mothers transfers allergic responsiveness to the recipient neonates. We propose the NOVEL CONCEPT that immunoregulatory lipids in allergic mothers are transported to the offspring and that altered levels of these lipids in the offspring of allergic mothers mediate enhancement of offspring responsiveness to allergens. The following is the rationale for this novel concept: During allergic inflammation in humans and mice, lipid metabolites are altered. Maternal lipids can then across the placenta to the fetus or are in the mother's milk during nursing. Lipid metabolites regulate DC differentiation and function, and DCs mediate initiation of allergic disease. In addition, because we demonstrated that maternal supplementation with α- tocopherol (α-T) reduces or γ-tocopherol (γ-T) elevates allergic inflammation in offspring, we propose that early in life, consumption of α-T and γ-T modulate endogenous lipid metabolites in allergic mothers that then regulate the development of offspring DC subsets that are critical for allergies in offspring. Consistent with our novel concept, our preliminary data demonstrate an increase in pro-inflammatory lipids and a decrease an anti- inflammatory lipids in the plasma and placentas of allergic mothers on mouse gestational day 18 (GD18). The decrease in anti-inflammatory lipid metabolites was blocked by maternal diet supplementation α-T. Thus, our central HYPOTHESIS is that maternal lipid metabolites elevate numbers of DCs in the fetus and neonate and that α-T reduces and γ-T elevates lipid metabolites that regulate 1) allergic responses and 2) DC subsets during the initiation of allergic lung responses. Aim 1. Test the hypothesis that, in allergic mothers, there are changes in pro-inflammatory lipid metabolites and anti-inflammatory lipid metabolites that can be transferred across the placenta to the fetus and in the milk to neonates. We will also determine whether the exogenous supplementation with α-T inhibits and γ-T elevates the generation of the endogenous lipid metabolites. Aim 2. Test the hypothesis that altered pro-inflammatory and anti-inflammatory lipid metabolites in allergic mothers regulate offspring development of DCs and allergic inflammation. It will also be determined whether human cord blood plasma lipid metabolites associate with infant atopy, DC numbers and DC function. Aim 3. Test the hypothesis that the lipid metabolites, which are altered in allergic mothers, regulate DCs in vitro. Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms of maternal lipid regulation of offspring DCs during development of allergies and 2) the design of future clinical studies. Furthermore, this may lead to novel interventions that significantly impact risk for allergic disease.

在动物和人类中，过敏母亲的后代对过敏原的反应性增强。我们尚不清楚过敏母亲中增加后代过敏原反应性的介质。证明过敏小鼠的胎儿肝脏和后代的不同 DC 亚群数量有所增加。将脾树突状细胞（DC）从过敏母亲的新生儿转移到非过敏母亲的受体新生儿过敏的母亲会将过敏反应转移给受体新生儿。过敏母亲体内的免疫调节脂质被转运给后代并改变的概念过敏母亲的后代中这些脂质的水平介导了后代对以下是这个新概念的基本原理：在人类和过敏性炎症期间。小鼠体内的脂质代谢物发生改变，然后可以穿过胎盘到达胎儿或体内。哺乳期间母乳中的脂质代谢物调节 DC 的分化和功能，DC 介导。此外，因为我们证明孕妇补充α-。生育酚 (α-T) 会减少或 γ-生育酚 (γ-T) 会增加后代的过敏性炎症，我们建议尽早在生活中，摄入α-T和γ-T会调节过敏母亲的内源性脂质代谢物，然后调节对后代过敏至关重要的后代 DC 亚群的发育，与我们的一致。新概念，我们的初步数据表明促炎脂质增加，抗炎脂质减少小鼠妊娠第 18 天（GD18）过敏母亲血浆和胎盘中的炎性脂质。母亲饮食补充 α-T 可以阻止抗炎脂质代谢物的减少。中心假设是母体脂质代谢物会增加胎儿和新生儿中 DC 的数量， α-T 降低脂质代谢物，γ-T 升高脂质代谢物，调节 1) 过敏反应和 2) DC 亚群在过敏性肺部反应开始期间目标 1. 检验过敏性母亲中存在的假设。可转移的促炎脂质代谢物和抗炎脂质代谢物的变化通过胎盘到达胎儿并在乳汁中到达新生儿。我们还将确定是否是外源性的。补充 α-T 会抑制内源性脂质代谢物的产生，而 γ-T 会增加内源性脂质代谢物的产生。检验改变过敏母亲的促炎和抗炎脂质代谢物的假设调节DCs的后代发育和过敏性炎症也将被确定。脐带血血浆脂质代谢与婴儿特应性、DC 数量和 DC 功能相关。过敏母亲体内脂质代谢物发生改变，在体外调节 DC 的假设已成功。这些研究的完成将对 1）我们对孕产妇机制的理解产生重大影响。子代 DC 在过敏发展过程中的脂质调节；2）未来临床研究的设计。此外，这可能会导致新的干预措施显着影响过敏性疾病的风险。