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

• 批准号: 9323656
• 负责人: JOAN M COOK-MILLS
• 金额: $ 55.08万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/9323656
• 关键词: Allergens; Allergic; Allergic Disease; Allergic inflammation; Animals; Anti-Inflammatory Agents; Anti-inflammatory; 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; Nurses; 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; neonate; novel; octadecadienoic acid; offspring; particle; pregnant; response

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。母亲的 过敏母亲中增加后代过敏原反应性的介质尚不清楚。我们 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传递给受孕新生儿。我们建议小说 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 过敏原。以下是这个新概念的基本原理：在人类和过敏性炎症期间 小鼠的脂质代谢发生了改变。然后，母体脂质可以穿过胎盘到达胎儿或存在于胎儿体内。 哺乳期间的母乳。脂质代谢物调节 DC 分化和功能，DC 介导 过敏性疾病的发生。此外，因为我们证明母亲补充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。这 母亲饮食补充 α-T 可以阻止抗炎脂质代谢物的减少。因此，我们的 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 在肺部过敏反应开始期间。目标 1. 检验以下假设：在过敏的母亲中，有 可转移的促炎脂质代谢物和抗炎脂质代谢物的变化 穿过胎盘到达胎儿，并通过乳汁到达新生儿。我们还将确定是否存在外源性 补充 α-T 会抑制内源性脂质代谢物的产生，而 γ-T 则会增加内源性脂质代谢物的产生。目标2。 检验改变过敏母亲的促炎和抗炎脂质代谢物的假设 调节 DC 的后代发育和过敏性炎症。还将确定人类是否 脐带血血浆脂质代谢与婴儿特应性、DC 数量和 DC 功能相关。目标 3. 测试 假设过敏母亲中发生改变的脂质代谢物在体外调节树突状细胞。成功的 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。