Targeting trained immunity and Th1/Th17 axis with combination adjuvants

使用组合佐剂针对经过训练的免疫力和 Th1/Th17 轴

• 批准号: 10220416
• 负责人: Maziar Divangahi
• 金额: $ 60万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-26 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220416
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Agonist; Attenuated Vaccines; Automobile Driving; Biological Models; Cells; Communicable Diseases; Data; Epigenetic Process; Goals; Health; Helper-Inducer T-Lymphocyte; Hematopoietic stem cells; Human; Immune; Immune response; Immunity; Infection; Longevity; Lymphoid; Macaca; Macaca mulatta; Macrophage Activation; Malaria; Maps; Mediating; Memory; Modeling; Multipotent Stem Cells; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Myelogenous; Natural Immunity; Outcome; Pathway interactions; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Population; Reporter; Resistance; T cell differentiation; TLR7 gene; Testing; Training; Translating; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; adaptive immune response; beta-Glucans; cell type; dectin 1; effector T cell; improved; in vitro Model; in vivo; macrophage; metabolic profile; monocyte; mouse model; nanoemulsion; novel; pathogen; pre-clinical; prevent; protective efficacy; response; vaccine development; vaccine efficacy; vaccine-induced immunity

PROJECT SUMMARY/ABSTRACT The lack of effective vaccines against most infectious diseases is largely a result of our fundamental lack of understanding of mechanisms involved in protective immunity. Adjuvants incorporated into vaccine formulations have a major impact on vaccine efficacy via modulating and prolonging host immune responses; however, our understanding of their underlying mechanism(s) of action in driving specific immune parameters is incomplete. While vaccines are the most effective way to prevent and control infectious diseases, many pathogens that significantly impact human health remain without an effective vaccine. For example, one-fourth of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB)1, the leading infectious disease killer in the world. It is likely that for TB, and other major infectious diseases (e.g. AIDS and malaria), new adjuvants or adjuvant combinations will be essential for instructing a protective immune response. We and others have shown that targeting both the type 1 T helper (Th1) cells and type 17 T helper (Th17) cells enhance vaccine-induced immunity for TB5-8. Additionally, we have recently demonstrated that live vaccines (e.g. BCG) and adjuvants (e.g. β-glucan) generate innate memory response, termed trained immunity, via epigenetic reprogramming of monocytes/macrophages, thereby conferring protection against Mtb infection9,10. These data together suggest that combination adjuvants targeting both innate trained immunity and adaptive Th1/Th17 cellular responses can enhance protective immunity against pathogens. Thus, defining the mechanisms of action of combination adjuvants that generate potent trained immunity and protective Th1/Th17 axis, are the overall goals of this proposal. In the current proposal, we hypothesize that combinations of adjuvants that drive Th1 responses (AS01 or UM-1007, a novel TLR7/8 agonist) and Th17 responses (β- glucan, nanoemulsion, or UM-1098, a novel Mincle agonist) will result in Th1/Th17 adaptive responses and/or enhance trained immunity. We will achieve these overall goals through the following four Specific Aims. Specific Aim 1: To determine the mechanisms by which combination adjuvants elicit Th1/Th17 immune responses. Specific Aim 2. To determine the impact of combination adjuvants on hematopoietic stem cells and trained immunity. Specific Aim 3. To determine whether use of combination adjuvants improves recall Th1/Th17 responses and trained immunity upon challenge. Specific Aim 4. Determine the mechanism of action of combination adjuvants in a pre-clinical human-like rhesus macaque model. Together, the aims of this study will map out the pathways induced by combination of adjuvants that effectively drive Th1/Th17 responses and trained immunity. Through Mtb challenge studies, we will demonstrate whether the mechanisms by which Th1/Th17 and trained immunity are elicited are involved in protection against pathogen challenge. While we will use TB as a model system, we envision that dissecting the mechanism of adjuvants-mediated immunity has broader impact on many other infectious diseases.

项目摘要/摘要 缺乏针对大多数传染病的有效疫苗在很大程度上是由于我们根本缺乏 了解涉及保护免疫的机制。结合到疫苗公式中的调节器 通过调节和延长宿主免疫回报对疫苗效率产生重大影响；但是，我们的 了解其在驱动特定免疫参数中的作用的基本机制是不完整的。 疫苗是预防和控制传染病的最有效方法，但许多病原体 没有有效的疫苗，显着影响人类健康仍然存在。例如，世界四分之一 人口受到结核分枝杆菌（MTB）的潜在感染，结核病的病因（TB）1， 世界领先的传染病杀手。结核病和其他主要的传染病可能很可能（例如 艾滋病和疟疾），新的佐剂或辅助组合对于指导受保护的免疫至关重要 回复。我们和其他人已经表明，针对1型辅助器（TH1）细胞和17 t助手 （TH17）细胞增强了疫苗诱导的TB5-8免疫力。此外，我们最近证明了现场 疫苗（例如BCG）和调节器（例如β-葡聚糖）产生先天记忆反应，称为训练有素的免疫功能， 通过对单核细胞/巨噬细胞的表观遗传重编程，从而对MTB进行了保护 感染9,10。这些数据一起表明，组合可以调整针对两个先天训练的免疫功能 自适应TH1/TH17细胞反应可以增强针对病原体的保护性免疫学。那， 定义组合调节器的作用机制，这些作用会产生强大的训练免疫和保护性 TH1/TH17轴是该提案的总体目标。在当前的建议中，我们假设该组合 驱动Th1响应（AS01或UM-1007，新型TLR7/8激动剂）和Th17响应的调节器（β-） 葡聚糖，纳米乳液或UM-1098，一种新颖的小动物）将导致Th1/Th17自适应反应和/或 增强训练有素的免疫力。我们将通过以下四个特定目标实现这些总体目标。具体的 目标1：确定组合调整引起的TH1/TH17免疫调查的机制。 具体目的2。确定组合调节器对造血干细胞的影响并训练 免疫。特定目的3。确定组合的使用是否适应改善召回th1/th17 挑战时的反应和训练的免疫力。特定目的4。确定作用机理 在类似人类的恒河猕猴模型中的组合调节器。一起，这项研究的目的将 绘制有效驱动TH1/TH17响应并训练的调节器的组合引起的途径 免疫。通过MTB挑战研究，我们将证明TH1/TH17和 引起训练的免疫力参与了防止病原体挑战的保护。虽然我们将使用结核 模型系统，我们设想剖析调节器介导的免疫力的机制具有更大的影响 在许多其他传染病上。