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

在动物和人类中，过敏母亲的后代对过敏原的反应性增加。母性的 过敏母亲的中介物增加了后代对过敏原的反应，目前尚不清楚。我们 结果表明，过敏小鼠的胎肝和后代的DC亚群数量增加。 从过敏母亲的新生儿向非过敏母亲的受体新生儿移植脾树突状细胞 过敏性母亲会将过敏反应传递给接受者的新生儿。我们建议写一部小说 过敏母亲的免疫调节脂质被运输到后代并改变的概念 过敏性母亲的后代中这些脂质的水平介导了后代对 过敏原。以下是这一新概念的基本原理：在人类过敏性炎症和 小鼠，脂类代谢产物发生改变。然后，母体的脂质可以通过胎盘到达胎儿或在 哺乳期间的母乳。脂代谢产物调节DC的分化和功能，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)降低或γ-生育酚(γ-T)升高子代过敏性炎症，我们建议及早 在生活中，α-T和γ-T的摄入调节过敏母亲的内源性脂质代谢产物，然后 调节后代DC亚群的发育，而DC亚群对后代过敏至关重要。与我们的 新的概念，我们的初步数据显示，促炎脂质增加，而抗炎 小鼠妊娠第18天过敏母亲血浆和胎盘中的炎性脂质。这个 母体饮食补充α-T可阻断抗炎脂代谢产物的减少。因此，我们的 中心假设是母体脂质代谢产物增加了胎儿和新生儿中DC的数量，并 α-T降低和γ-T升高脂代谢产物调节1)过敏反应和2)DC亚群 在肺部过敏反应的启动过程中。目标1.测试假设，在过敏的母亲中，有 可转运的促炎性和抗炎性脂代谢产物的变化 通过胎盘传给胎儿，并在乳汁中传给新生儿。我们还将确定外源的 补充α-T可抑制内源性脂质代谢产物的生成，而补充γ-T可增加内源性脂质代谢产物的生成。目标2. 检验过敏母亲的促炎和抗炎脂代谢产物改变的假说 调节子代DC的发育和过敏性炎症。还将确定人类是否 脐血脂代谢产物与婴儿特应性疾病、DC数量及DC功能相关。目标3.测试 假设过敏性母亲体内的脂代谢产物在体外调节树突状细胞。成功 这些研究的完成将对1)我们对母体致病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以及2)未来临床研究的设计。 此外，这可能导致新的干预措施，显著影响过敏性疾病的风险。

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.