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: 10533157
• 负责人: Christopher M Jewell
• 金额: $ 5.83万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533157
• 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; rational design; response; self assembly; trafficking; translational potential; 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展之一，可以预防感染， 单剂量。然而，针对继续挑战公共卫生的疾病的疫苗必须诱导免疫， 反应不仅是有效的，但表现出可调的功能，如对细胞的极化反应， 介导的或抗体介导的免疫，促进免疫记忆超过效应子应答，或指导 免疫细胞到靶组织。佐剂可以通过激活特定的免疫途径来帮助实现这种控制， 或者说是一系列的途径，它们决定了抗原的反应。Toll样受体激动剂（TLRas），例如， 是一类不断增长的佐剂，其激活由分子引发的刺激性病原体传感途径。 在人类中不常见，但在病原体中常见。许多新的研究证实多功能或 能够激活几种TLR途径的组合佐剂在临床前驱动协同应答， 临床上然而，佐剂设计在历史上一直由经验方法主导。由此可见，新 简化疫苗组合物和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 沿着这些方面具有巨大的潜力，因为这些材料提供了交付多种货物的能力。 然而，许多材料-例如聚合物颗粒-表现出可以激活 炎症途径，即使在没有其他免疫线索的情况下。这一特点可以在疫苗接种中加以利用， 而且还阻碍了合理的设计，因为每个疫苗组分的作用被内在效应所模糊， 的承运人。提供生物材料特征的材料-例如共输送-但提高了模块化 和疫苗的定义可以提供关于联合佐剂如何增强免疫力的新知识， 为新一代疫苗的设计提供了信息，这些疫苗可以引发可调节的反应。为了实现这一目标，我们设计了 一种基于完全由免疫信号组装的多层膜（PEM）的新型疫苗。 这些免疫PEM（iPEM）是由肽抗原和聚离子TLRa静电自组装而成的 作为分子佐剂。在这个项目中，我们将测试的假设，并置抗原 iPEM中的TLRas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)根据iPEM中TLRas类型和组成，测试iPEM是否抑制T和B细胞功能，3）确定 iPEM组合物如何驱动LN的局部重组和T细胞迁移的变化，4）使用黑素瘤作为 测试床以评估iPEM作为TLRa组合的函数的功效。重要的是，我们将基准 这些材料对抗有效的生物材料疫苗载体和对抗临床相关的佐剂。我们的工作 将产生关于抗原和佐剂的并列和组合如何促进和 免疫学，为支持更合理的疫苗设计策略提供新的见解。