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加。产妇 增加后代中过敏原反应性的过敏母亲的介质尚不清楚。我们 表明，胎儿肝脏和后代的过敏性小鼠有不同的DC亚群的数量增加。 从过敏母亲的新生儿向非过敏母亲的受体新生儿转移脾树突状细胞（DC） 过敏性母亲将过敏性反应传递给受体新生儿。我们建议小说 概念：过敏母亲体内的免疫调节脂质被转运至后代， 过敏母亲的后代中这些脂质的水平介导后代对以下物质的反应性增强： 过敏原以下是这一新概念的基本原理：在人类过敏性炎症期间， 在小鼠中，脂质代谢物被改变。母体脂质然后可以通过胎盘到达胎儿或在胎盘中。 母乳喂养期间脂质代谢产物调节DC分化和功能，DC介导 引发过敏性疾病。此外，因为我们证明了母体补充α- 生育酚（α-T）减少或γ-生育酚（γ-T）增加后代的过敏性炎症，我们认为， 在生活中，α-T和γ-T消耗调节过敏母亲的内源性脂质代谢， 调节对后代过敏至关重要的后代DC亚群的发育。符合我们 新概念，我们的初步数据表明，增加促炎脂质和减少抗炎 在小鼠妊娠第18天（GD 18），过敏母亲的血浆和胎盘中的炎性脂质。的 母体饮食补充α-T可阻断抗炎脂质代谢产物的减少。所以我们 中心假设是母体脂质代谢物增加了胎儿和新生儿中DC的数量， α-T降低和γ-T升高调节1）过敏反应和2）DC亚群的脂质代谢物 在过敏性肺反应的开始期间。目标1。测试假设，在过敏的母亲，有 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，然后进入乳汁到达新生儿。我们还将确定外源性 补充α-T可抑制内源性脂质代谢产物的生成，而补充γ-T可提高内源性脂质代谢产物的生成。目标二。 测试过敏母亲中促炎和抗炎脂质代谢物改变的假设 调节后代DCs的发育和过敏性炎症。它也将确定是否人类 脐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 这一假说认为，在过敏性母体中发生改变的脂质代谢物在体外调节DC。成功 这些研究的完成将对1）我们对孕产妇死亡机制的理解产生重大影响。 在变态反应发展过程中后代DC的脂质调节和2）未来临床研究的设计。 此外，这可能导致新的干预措施，显着影响过敏性疾病的风险。