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(PR3) 早期生命中的免疫发育(理想)是动态的，越来越多的证据表明，它影响 常见不良临床表型的风险，包括低疫苗反应性和倾向于 呼吸道感染和/或哮喘。然而，关于确切的机制或如何重定向，人们知之甚少 免疫发育到更有利的表型。波士顿儿童医院的精密疫苗计划(PVP) 医院(BCH)已经开发出尖端的人类体外试验，模拟与年龄相关的白细胞变化 功能--即免疫个体发育和群体(如年龄)--特定的影响和作用机制 免疫调节剂，包括代谢物、蛋白质、佐剂和疫苗。 项目3(PR3)将利用人体体外建模来深入了解 与观察到的临床表型有关。我们已公布和未公布的初步数据表明，我们的 节省样本的人体体外分析平台可以模拟婴儿和婴儿的先天和获得性免疫反应 幼儿因年龄和疾病状况不同而不同。我们的假设是，我们在体外的先天和适应性 建模平台可以有意义地询问与内型相关的分子信号通路 (疾病亚型)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尖端的人类体外测试系统来模拟人类免疫细胞 对婴儿疫苗的反应，以及确认、评估和翻译在PR1和PR中确定的途径 2.我们将通过实现以下具体目标来实现这一目标：SA1。评估机制 潜在的理想内型。在这个目标中，我们将对通路、生物标记物、 在PR1和PR2中发现的代谢物。SA2.识别免疫调节剂，从 不利于有利的内型。我们将对免疫激活进行建模，以响应能够重新启动 塑造免疫内型，包括影响已确定的相关内型相关途径的药物 在PR1和PR2中。 总体而言，PR3的成功完成将为疫苗相关的理想提供新的见解 反应性、感染和/或哮喘倾向。这一努力将提供对理想的机械性洞察，帮助 确认和探测在Pr1和Pr2中识别的新的预后生物标志物和通路，并识别药物(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 与低疫苗反应性、呼吸道感染和/或哮喘相关的内型 轨迹和内型，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 Our published and unpublished preliminary data indicate that our sample-sparing human in vitro assay platforms can model innate and adaptive immune responses of infants and young children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.