Targeting trained immunity and Th1/Th17 axis with combination adjuvants

项目总结/摘要 对大多数传染病缺乏有效的疫苗主要是由于我们根本缺乏 了解保护性免疫的机制。掺入疫苗制剂中的佐剂 通过调节和延长宿主免疫应答对疫苗效力产生重大影响;然而， 对它们在驱动特异性免疫参数中的潜在作用机制的理解是不完整的。 虽然疫苗是预防和控制传染病的最有效方法，但许多病原体， 对人类健康有重大影响仍然没有有效疫苗。例如，世界上四分之一的 人群潜伏感染结核分枝杆菌（Mtb），结核病（TB）的病原体1， 世界上最大的传染病杀手对于结核病和其他主要传染病（例如， 艾滋病和疟疾），新的佐剂或佐剂组合将是必不可少的指导保护性免疫 反应我们和其他人已经表明，靶向1型辅助性T细胞（Th 1）和17型辅助性T细胞， （Th 17）细胞增强疫苗诱导的对TB 5 -8的免疫。此外，我们最近还证明， 疫苗（例如卡介苗）和佐剂（例如β-葡聚糖）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 感染9，10.这些数据共同表明，靶向先天训练免疫和先天训练免疫的联合佐剂 适应性Th 1/Th 17细胞应答可以增强针对病原体的保护性免疫。因此，在本发明中， 确定产生有效训练免疫和保护性免疫的组合佐剂的作用机制， Th 1/Th 17轴是本提案的总体目标。在目前的提案中，我们假设， 佐剂驱动Th 1应答（AS 01或UM-1007，一种新型TLR 7/8激动剂）和Th 17应答（β- 葡聚糖、纳米乳剂或UM-1098，一种新型Mincle激动剂）将导致Th 1/Th 17适应性应答和/或 增强训练免疫力。我们将通过以下四个具体目标来实现这些总体目标。具体 目的1：确定联合佐剂诱导Th 1/Th 17免疫应答的机制。 具体目标2。为了确定联合佐剂对造血干细胞的影响， 免疫力具体目标3。确定联合佐剂的使用是否改善Th 1/Th 17的回忆 在挑战时的反应和训练的免疫力。具体目标4。确定的作用机制 在临床前人样恒河猴模型中使用组合佐剂。总之，本研究的目的将 绘制出佐剂组合诱导的有效驱动Th 1/Th 17应答的途径， 免疫力通过Mtb攻击研究，我们将证明Th 1/Th 17和 训练的免疫力被引发，参与抵抗病原体攻击的保护。虽然我们将结核病作为一种 模型系统，我们设想，解剖的机制，免疫调节剂介导的免疫具有更广泛的影响 在许多其他传染病上。

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.