Programming immune function through modular assembly of polyionic immune signals

通过聚离子免疫信号的模块化组装来编程免疫功能

• 批准号: 10064629
• 负责人: Christopher M Jewell
• 金额: $ 33.65万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064629
• 关键词: Adjuvant; Adoptive Transfer; Agonist; Antibodies; Antibody-mediated protection; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Beds; Benchmarking; Biocompatible Materials; Biodistribution; Cell physiology; Cells; Characteristics; Clinical; Complex; Cues; Data; Differentiation Antigens; Disease; Dose; Electrostatics; Endosomes; Excision; Exhibits; Film; Formulation; Generations; Glycolic-Lactic Acid Polyester; Goals; Heating; Histology; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunologic Memory; Immunologic Tests; Immunologics; In Vitro; Individual; Infection; Infection prevention; Inflammatory; Kinetics; Knowledge; Length; Link; Liposomes; Lymph Node Tissue; Lysosomes; Malignant Neoplasms; Mediating; Molecular; Mus; Nanostructures; Nature; Pathway interactions; Pattern; Peptides; Phenotype; Play; Polymers; Population; Process; Property; Public Health; Reporting; Role; SILV gene; Serum; Signal Pathway; Signal Transduction; Solvents; Specificity; Spleen; Stains; Stromal Change; Structure; T-Lymphocyte; TLR3 gene; Technology; Testing; Therapeutic; Tissues; Toll-like receptors; Transgenic Organisms; Vaccination; Vaccine Design; Vaccines; Work; antigen-specific T cells; aqueous; base; capsule; cell motility; clinically relevant; combat; controlled release; cytokine; density; design; immune function; immunogenicity; improved; insight; lymph nodes; melanoma; mouse model; nanoparticle; nanotechnology platform; novel vaccines; particle; pathogen; polyion; pre-clinical; prevent; programs; response; self assembly; trafficking; tumor; uptake

Vaccination is one of the transformative advances of the last century, allowing prevention of infection with a single dose. However, vaccines for diseases that continue to challenge public health must induce immune responses that are not only potent, but that exhibit tunable features such as polarizing responses toward cell- mediated or antibody-mediated immunity, promoting immunological memory over effector response, or directing immune cells to target tissue. Adjuvants could help deliver this control by activating specific immune pathways, or sets of pathways, that define how antigens are responded to. Toll-like receptor agonists (TLRas), for example, are a growing class of adjuvants that activate stimulatory pathogen-sensing pathways triggered by molecular patterns uncommon in humans, but common in pathogens. Many new studies confirm multifunctional or combination adjuvants able to activate several TLR pathways drive synergistic responses pre-clinically and clinically. However, adjuvant design has historically been dominated by empirical approaches. Thus, new strategies that simplify vaccine composition and create modular platforms for delivery of multiple adjuvants could generate insight into how adjuvants control the nature of immune function, individually or in concert. Biomaterials hold great potential along these lines because these materials offer the ability to deliver multiple cargos. However, many materials – polymer particles, for example – exhibit intrinsic features that can activate inflammatory pathways even in the absence of other immune cues. This feature can be harnessed in vaccination, but also hinders rational design because the role of each vaccine component is clouded by the intrinsic effects of the carrier. Materials that offer features of biomaterials – such as co-delivery – but that improve the modularity and definition of vaccines could provide new knowledge of how combination adjuvants polarize immunity and inform the design of a new generation of vaccines that elicit tunable responses. Toward this goal, we designed a new class of vaccine based on polyelectrolyte multilayers (PEMs) assembled entirely from immune signals. These immune-PEMs (iPEMs) are electrostatically self-assembled from peptide antigens and polyionic TLRas that serve as molecular adjuvants. In this project we will test the hypothesis that juxtaposition of antigens and TLRas in iPEMs can be used to program specific features of antigen-specific immunity. The specific aims are: 1) test if TLRa composition in iPEM correlates to in vitro TLR signaling & polarizes DC/T cell function, 2) test if iPEMs polarize T and B cell function depending on TLRas type and composition in iPEMs, 3) determine how iPEM composition drives local reorganization of LNs & changes in T cell migration, 4) use melanoma as a test bed to assess the efficacy of iPEMs as a function of TLRa combination. Importantly, we will benchmark these materials against potent biomaterial vaccines carriers, and against clinically-relevant adjuvants. Our work will generate new knowledge of how the juxtaposition and combination of antigens and adjuvants promote and polarize immunity, contributing new insight to support more rational vaccine design strategies.

疫苗接种是上个世纪的变革性进步之一，可以通过疫苗来预防感染 单剂量。然而，针对持续挑战公共卫生的疾病的疫苗必须诱导免疫 反应不仅有效，而且表现出可调节的特征，例如对细胞的极化反应 介导或抗体介导的免疫，促进免疫记忆超过效应反应，或指导 免疫细胞攻击目标组织。佐剂可以通过激活特定的免疫途径来帮助实现这种控制， 或一组路径，定义了抗原如何反应。 Toll样受体激动剂(TLRas)，例如， 是一类不断增长的佐剂，可激活由分子触发的刺激性病原体感应途径 模式在人类中不常见，但在病原体中常见。许多新研究证实多功能或 能够激活多种 TLR 通路的组合佐剂可在临床前和临床前驱动协同反应 临床上。然而，辅助设计历来以经验方法为主。因此，新 简化疫苗成分并创建用于递送多种佐剂的模块化平台的策略可以 深入了解佐剂如何单独或协同控制免疫功能的性质。生物材料 在这些方面具有巨大的潜力，因为这些材料能够运送多种货物。 然而，许多材料（例如聚合物颗粒）表现出可以激活的内在特征 即使在没有其他免疫信号的情况下，炎症途径也能发挥作用。该功能可用于疫苗接种， 但也阻碍了合理设计，因为每种疫苗成分的作用都被其内在效应所掩盖 承运人的。具有生物材料特性（例如共同交付）但提高模块化性的材料 疫苗的定义可以提供关于组合佐剂如何极化免疫和 为引发可调节反应的新一代疫苗的设计提供信息。为了这个目标，我们设计了 一种基于完全由免疫信号组装的聚电解质多层（PEM）的新型疫苗。 这些免疫 PEM (iPEM) 由肽抗原和聚离子 TLR 静电自组装而成 用作分子佐剂。在这个项目中，我们将测试抗原并置的假设 iPEM 中的 TLRas 可用于对抗原特异性免疫的特定功能进行编程。具体的 目的是：1) 测试 iPEM 中的 TLRa 成分是否与体外 TLR 信号传导相关并极化 DC/T 细胞功能， 2) 测试 iPEM 是否根据 iPEM 中的 TLRas 类型和成分极化 T 和 B 细胞功能，3) 确定 iPEM 成分如何驱动 LN 的局部重组和 T 细胞迁移的变化，4) 使用黑色素瘤作为 评估 iPEM 功效作为 TLRa 组合函数的测试台。重要的是，我们将进行基准测试 这些材料针对有效的生物材料疫苗载体以及临床相关佐剂。我们的工作 将产生关于抗原和佐剂的并置和组合如何促进和 极化免疫，为支持更合理的疫苗设计策略提供新的见解。