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增加。母亲 尚不清楚提高后代过敏原反应性的过敏母亲的介体尚不清楚。我们 证明过敏小鼠的胎儿肝脏和后代具有不同的DC子集的数量。 脾脏树突状细胞（DC）从过敏母亲的新生儿转移到非非 - 过敏母亲将过敏反应转移到接受者新生儿。我们提出了小说 过敏母亲中免疫调节脂质的概念被转移到后代而改变 这些脂质的水平在过敏母亲媒体的后代增强了后代反应能力 过敏原。以下是这个新颖概念的理由：在人类过敏性注射期间 小鼠，脂质代谢产物改变。然后 母亲的牛奶在护士期间。脂质代谢物调节直流分化和功能，DC介导 过敏性疾病的启动。另外，因为我们证明了补充α-的材料 生育酚（α-T）降低或γ-生育酚（γ-T）升高后代的过敏性炎症，我们提出早期的提议 在生活中，消耗α-T和γ-T调节过敏母亲的内源性脂质代谢产物 规范对后代过敏至关重要的后代DC子集的发展。与我们一致 新颖的概念，我们的初步数据表明，促炎脂质的增加，抗 - 小鼠妊娠第18天（GD18）的血浆和斑点中的炎性脂质。 抗炎脂质代谢产物的降低通过补充物质饮食α-T阻断。那，我们的 中心假设是，Mater脂质代谢产物增加了胎儿和新生儿中的DC数量 α-T降低，γ-T升高调节的脂质代谢产物1）过敏反应和2）DC子集 在过敏性肺反应的倡议中。目的1。检验以下假设：在过敏母亲中，有 可以转移的促炎性脂质代谢物和抗炎脂质代谢产物的变化 穿过胎儿到胎儿和牛奶到新生儿。我们还将确定是否外源 补充α-T抑制和γ-T可以提高内源性脂质代谢产物的产生。目标2。 检验了改变过敏母亲中促炎和抗炎脂质代谢物的假设 调节DCS和过敏性注射的后代发展。还将确定人类是否 脐带血等离子体脂质代谢物与婴儿特应性，直流数和直流功能相关。目标3。测试 假设在过敏母亲中改变的脂质代谢产物在体外调节DC。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 后代DC在过敏过程中的脂质调节和2）未来临床研究的设计。 此外，这可能会导致新的干预措施，从而显着影响过敏性疾病的风险。