In Utero Sensitization to Allergens & Pollution

以实验室为基础的呼吸力学研究项目机械研究项目：子宫对过敏原的敏化和环境污染物的作用。最近的证据表明，抗原致敏，定义为抗原诱导的脐血单个核细胞(CPMC)增殖试验，发生在产前。例如，我们的工作证明，抗原诱导的CBMC增殖发生在多个吸入室内变应原的体外刺激下，这些变应原在市中心普遍存在，包括蟑螂和老鼠。其他实验研究表明，柴油废气颗粒物(DEP)，特别是DEP中的多环芳烃(PAH)成分，可以增强抗原特异性敏化和 免疫球蛋白介导的过程。特别是考虑到曼哈顿北部和其他地方环境室内过敏原和DEP的高流行率，以及它们在哮喘中的明显作用，子宫内抗原特异性免疫反应的发生可能对随后的呼吸道疾病的发生具有重要意义。然而，产前致敏对哮喘随后的气道高反应性和抗原诱导的炎症特征的影响尚不清楚。此外，环境污染物(如DEP、内毒素)对产前抗原特异性致敏开始的重要性也尚未阐明。该项目将检验以下假设：宫内致敏会增加随后的呼吸道高反应性和抗原诱导的炎症的风险，环境暴露于DEP会促进宫内抗原特异性致敏，而暴露于内毒素具有保护作用。目的是利用小鼠模型来确定宫内敏化对随后的呼吸道高反应性和炎症的重要性，并确定宫内敏化的机制是否涉及多个城市环境暴露的相互作用。最终，这些研究可能导致对哮喘发病机制的更好理解，并最终为哮喘预防提供更好的策略。具体地说，目标是： 目的1.确定宫内致敏是否会增加随后的呼吸道高反应性和抗原诱导的炎症的风险。 目的2.确定曼哈顿北部环境特有的DEP是否促进抗原特异性的产前敏化，以及这是否通过上调Th2介导的过敏反应而发生。我们还将确定通过肺组织中的PAH加合物测量的PAH是否介导了这一反应。 目的3.确定内毒素是否能阻止抗原特异性产前致敏反应的发生，以及这种保护作用是否通过上调Th1介导的免疫过程来实现。

The Laboratory-Based Respiratory Mechanistic Research Project Mechanistic Research Project: In Utero Sensitization to Allergens and the Role of Environmental Pollutants. Recent evidence suggests that antigen sensitization, defined as antigen-induced cord blood mononuclear cell (CPMC) proliferation assays, occurs prenatally. For example, our work demonstrates that antigen-induced CBMC proliferation occurs following in vitro stimulation with multiple inhaled indoor allergens prevalent in inner-cities, including cockroach and mouse. Other experimental research has indicated that diesel exhaust particulates (DEP), and particularly the polycyclic aromatic hydrocarbon (PAH) component of DEP, can augment antigen-specific sensitization and IgE-mediated processes. The occurrence of antigen-specific immune responses in utero may have important implications for the subsequent onset of respiratory disease, particularly in light of the high prevalence of both environmental indoor allergens and DEP in northern Manhattan and elsewhere, and their apparent role in asthma. Yet the effect of prenatal sensitization on subsequent airway hyperreactivity and antigen-induced inflammation characteristic of asthma is not understood. In addition, the importance of environmental pollutants (egs DEP, endotoxin) to the onset of prenatal antigen-specific sensitization also has not been elucidated. The project will test the hypotheses that in utero sensitization increases the risk for subsequent airway hyperreactivity and antigen-induced inflammation, and that environmental exposure to DEP promotes antigen-specific sensitization in utero, whereas exposure to endotoxin is protective. The goal is to use mouse models to determine the importance of in utero sensitization to subsequent airway hyperreactivity and inflammation, and to determine whether the mechanism of in utero sensitization involves the interaction of multiple urban environmental exposures. Ultimately, these studies could lead to a better understanding of asthma pathogenesis, and ultimately better strategies for asthma prevention. Specifically, the aims are to: Aim 1. Determine whether in utero sensitization increases the risk for subsequent airway hyperreactivity and antigen-induced inflammation. Aim 2. Determine whether DEP, endemic to the northern Manhattan environment, promote antigen-specific prenatal sensitization, and whether this occurs by upregulating Th2-mediated allergic responses. We will also determine whether PAH, measured by PAH-adducts in lung tissue, mediates this response. Aim 3. Determine whether endotoxin protects from the development of antigen-specific prenatal sensitization, and whether this occurs by upregulating Th1-mediated immune processes.