Project 3: In vitro modeling to define mechanisms of childhood vaccine response, susceptibility to respiratory infectious disease and asthma

项目摘要-项目3（PR 3） 生命早期的免疫发育（IDEAL）是动态的，越来越多的证据表明，它影响着生命早期的免疫发育。 常见不良临床表型的风险，包括低疫苗反应性和 呼吸道感染和/或哮喘。然而，关于精确的机制和如何重定向， 免疫发育到更有利的表型。波士顿儿童医院的精准疫苗计划（PVP） Hospital（BCH）开发了尖端的人体体外试验，该试验模拟了白细胞中与年龄相关的变化， 功能-即，免疫个体发育和群体（如年龄）特异性效应和作用机制 免疫调节剂，包括代谢物、蛋白质、佐剂和疫苗。 项目3（PR 3）将利用人类体外建模来深入了解 与观察到的临床表型相关。我们已发表和未发表的初步数据表明， 样品保留的人体外测定平台可以模拟婴儿的先天性和适应性免疫应答， 幼儿因年龄和疾病状况而异。我们的假设是，我们的先天和适应性在体外 建模平台可以有意义地询问与内型相关的分子信号传导途径， （疾病亚型）的临床表型，如疫苗反应性、呼吸道感染和/或 哮喘我们的目标是利用我们最先进的人体体外分析系统来模拟人体免疫细胞 对婴儿疫苗的反应以及确认、评估和翻译PR 1和PR中确定的途径 2.我们将通过追求以下具体目标来实现这一目标：评估机制 基础IDEAL内型。在这一目标中，我们将追求的分子审讯的途径，生物标志物， 在PR 1和PR 2中发现的代谢物。SA 2.识别免疫调节剂， 不利于有利的内型。我们将模拟免疫激活，以响应能够重新激活的试剂。 塑造免疫内型，包括影响已鉴定的相关内型相关途径的药物 在PR 1和PR 2。 总体而言，PR 3的成功完成将为IDEAL与疫苗的关系提供新的见解 反应性、感染和/或哮喘倾向。这项工作将提供对理想的机械洞察力，帮助 确认和探测在PR 1和PR 2中鉴定的新的预后生物标志物和途径，并鉴定试剂（例如， 蛋白质、代谢物、佐剂、疫苗），可以将人类婴儿白细胞从不利的 与低疫苗应答性、呼吸道感染和/或哮喘相关的内型， 从而促进儿童健康。

Project Summary – Project 3 (PR3) Immune development in early life (IDEAL) is dynamic and growing evidence suggests that it impacts the risk for common undesirable clinical phenotypes including low vaccine responsiveness, and proneness to respiratory infection and/or asthma. However, little is known regarding precise mechanisms nor how to redirect immune development to more favorable phenotypes. The Precision Vaccines Program (PVP) at Boston Children’s Hospital (BCH) has developed cutting-edge human in vitro assays which model age related changes in leukocyte function- i.e., immune ontogeny and population (e.g. age)-specific effects and mechanisms of action of immunomodulatory agents, including metabolites, proteins, adjuvants and vaccines. Project 3 (PR3) will leverage human in vitro modeling to gain insight into signaling pathways that are relevant to the clinical phenotypes observed. Our published and unpublished preliminary data indicate that our sample-sparing human in vitro assay platforms can model innate and adaptive immune responses of infants and young children which vary by age and disease status. Our hypothesis is that our innate and adaptive in vitro modeling platforms can meaningfully interrogate molecular signaling pathways relevant to endotypes (disease sub-types) of clinical phenotypes such as vaccine responsiveness, respiratory infection and/or asthma. Our goal is to leverage our cutting-edge human in vitro assay systems to model human immune cell responses to infant vaccines as well as to confirm, assess and translate the pathways identified in PR1 and PR 2. We will achieve this goal by pursuing the following Specific Aims (SAs): SA1. Assess mechanisms underlying IDEAL endotypes. In this aim we will pursue molecular interrogation of pathways, biomarkers, metabolites discovered in PR1 and PR2. SA2. Identify immunomodulators that re-direct trajectories from unfavorable to favorable endotypes. We will model immune activation in response to agents capable of re- shaping immune endotypes, including agents that impact the relevant endotype-associated pathways identified in PR1 and PR2 . Overall, successful completion of PR3 will provide fresh insight into IDEAL in relation to vaccine responsiveness, infection and/or asthma proneness. This effort will provide mechanistic insight into IDEAL, help confirm and probe novel prognostic biomarkers and pathways identified in PR1 and PR2, and identify agents (e.g., proteins, metabolites, adjuvants, vaccines) that can redirect human infant leukocytes away from unfavorable endotypes associated with low vaccine responsiveness, respiratory infection and/or asthma and towards favorable trajectories and endotypes thereby advancing child health.