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: 9889123
• 负责人: Christopher M Jewell
• 金额: $ 34.34万
• 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/9889123
• 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，允许预防感染 单剂量。但是，继续挑战公共卫生的疾病疫苗必须诱导免疫学 不仅潜在的反应，而且暴露了可调的特征，例如对细胞的偏振反应 介导或抗体介导的免疫动力学，促进对效应子反应的免疫记忆或指导 免疫细胞靶向组织。调整可以通过激活特定的免疫途径来帮助实现此控制 或一组途径，这些途径定义了抗原的反应方式。例如 是一类成长类的调节器，可激活由分子触发的刺激病原体传感途径 人类中的模式很少，但在病原体中很常见。许多新研究证实了多功能或 结合调节器可以激活多种TLR途径，以驱动预链链接和 临床上。但是，从历史上看，可调节的设计一直由经验方法主导。那是新的 简化疫苗组成并创建模块化平台以交付多个调节器的策略可以 洞悉探究者如何单独或共同控制免疫功能的性质。生物材料 沿着这些线保持着巨大的潜力，因为这些材料具有交付多颗圆柱的能力。 但是，例如，许多材料（例如聚合物颗粒）表现出可以激活的固有特征 即使没有其他免疫线索，炎症途径也是如此。可以在疫苗接种中利用此功能， 但也阻碍了理性的设计，因为每个疫苗成分的作用都被内在效应蒙上了阴影 载体。提供生物材料特征（例如共递送）的材料，但可以改善模块化 疫苗的定义可以提供有关组合如何两极化免疫力和 告知新一代疫苗的设计，这些疫苗会引起可调节的反应。朝向这个目标，我们设计了 一类新的基于聚电解质多层（PEM）的疫苗完全由免疫信号组装而成。 这些免疫PEM（IPEM）是从胡椒抗原和聚离子TLRA的静电自组装的 用作分子调节器。在这个项目中，我们将测试抗原并置的假设 IPEM中的TLRA可用于编程抗原特异性免疫的特定特征。具体 目的是：1）测试IPEM中的TLRA组成是否与体外TLR信号传导相关并极化DC/T细胞功能， 2）测试iPEMS是否根据iPem中的TLRAS类型和组成两极分化T和B细胞功能，3）确定 IPEM组成如何驱动LNS及其T细胞迁移变化的局部重组，4）使用黑色素瘤作为一种 测试床以评估iPEMS的效率随TLRA组合的函数。重要的是，我们将基准 这些材料针对潜在的生物材料疫苗载体，以及与临床上相关的调节器。我们的工作 将产生有关抗原和调节器的并置和组合如何促进和的新知识 极化免疫学，为支持更多理性的疫苗设计策略提供了新的见解。