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.

项目概要/摘要 缺乏针对大多数传染病的有效疫苗很大程度上是由于我们根本上缺乏 了解疫苗配方中涉及保护性免疫的机制。 然而，我们的研究通过调节和延长宿主免疫反应对疫苗功效产生重大影响； 对它们驱动特定免疫参数的潜在作用机制的理解还不完整。 虽然疫苗是预防和控制传染病最有效的方法，但许多病原体 例如，世界上四分之一的人仍然没有有效的疫苗，对人类健康产生重大影响。 人群潜伏感染结核分枝杆菌 (Mtb)，这是结核病 (TB)1 的病原体， 结核病和其他主要传染病（例如结核病）很可能是世界上主要的传染病杀手。 艾滋病和疟疾），新的佐剂或佐剂组合对于指导保护性免疫系统至关重要 我们和其他人已经证明，针对 1 型 T 辅助细胞 (Th1) 和 17 型 T 辅助细胞。 (Th17) 细胞可增强疫苗诱导的 TB5-8 免疫力。 疫苗（例如卡介苗）和佐剂（例如β-葡聚糖）会产生先天记忆反应，称为训练免疫， 通过单核细胞/巨噬细胞的表观遗传重编程，从而提供针对 Mtb 的保护 这些数据共同表明，针对先天免疫的组合佐剂。 适应性 Th1/Th17 细胞反应可以增强针对病原体的保护性免疫力。 确定组合佐剂的作用机制，这些佐剂可产生有效的训练免疫和保护作用 Th1/Th17 轴，是该提案的总体目标。在当前提案中，我们致力于这种组合。 驱动 Th1 反应（AS01 或 UM-1007，一种新型 TLR7/8 激动剂）和 Th17 反应（β- 葡聚糖、纳米乳剂或 UM-1098（一种新型 Mincle 激动剂）将导致 Th1/Th17 适应性反应和/或 我们将通过以下四个具体目标来实现这些总体目标。 目标 1：确定联合佐剂引发 Th1/Th17 免疫反应的机制。 具体目标 2. 确定组合佐剂对造血干细胞的影响并训练 具体目标 3. 确定联合佐剂的使用是否可以改善 Th1/Th17 的记忆。 具体目标 4. 确定攻击后的反应和训练有素的免疫力。 这项研究的目的是在临床前类人恒河猴模型中使用组合佐剂。 绘制出有效驱动 Th1/Th17 反应的佐剂组合诱导的途径，并进行训练 通过 Mtb 攻击研究，我们将证明 Th1/Th17 和 Th1/Th17 的机制是否有效。 训练有素的免疫力参与防御病原体挑战。 模型系统，我们设想剖析佐剂介导的免疫机制具有更广泛的影响 关于许多其他传染病。