Programming immune function through modular assembly of polyionic immune signals

疫苗接种是上个世纪的变革性进步之一，它使预防感染成为可能。 单剂。然而，继续挑战公共卫生的疾病疫苗必须诱导免疫。 反应不仅有效，而且表现出可调的特征，例如对细胞的极化反应- 介导的或抗体介导的免疫，促进免疫记忆而不是效应器反应，或引导 免疫细胞以靶向组织。佐剂可以通过激活特定的免疫途径来帮助实现这种控制， 或一组通路，它们定义了抗原是如何反应的。Toll样受体激动剂(TLRA)，例如， 是一类越来越多的佐剂，它们激活由分子触发的刺激性病原体感知通路 这种模式在人类中不常见，但在病原体中很常见。许多新的研究证实多功能或 能够激活多个TLR通路的联合佐剂在临床前和 从临床上看。然而，佐剂设计历史上一直被经验方法所主导。因此，新的 简化疫苗成分和创建用于输送多种佐剂的模块化平台的战略可能 洞察佐剂如何单独或协同控制免疫功能的性质。生物材料 沿着这些路线拥有巨大的潜力，因为这些材料提供了运送多种货物的能力。 然而，许多材料--例如聚合物颗粒--表现出可以激活的固有特征 即使在没有其他免疫信号的情况下，炎症途径也是如此。这一特征可以在疫苗接种中加以利用， 但也阻碍了合理的设计，因为每个疫苗组件的作用都被内在效应所掩盖 航空母舰的。提供生物材料功能的材料--例如联合交付--但改善了模块化 疫苗的定义可以提供关于联合佐剂如何使免疫两极分化和 为新一代疫苗的设计提供信息，以引起可调的反应。为了实现这个目标，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。 这些免疫膜(IPEM)是由多肽抗原和多离子TLRA静电自组装而成的 作为分子佐剂。在这个项目中，我们将检验一种假设，即抗原的并置 而iPEM中的TLRas可用于编程特定的抗原特异性免疫功能。具体的 目的是：1)测试IPEM中的TLRa成分是否与体外TLR信号转导和极化DC/T细胞功能有关， 2)测试iPEM中TLRAs的类型和组成是否使T和B细胞功能极化，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 试验台，以评估作为TLRa联合作用的iPEMS的疗效。重要的是，我们将制定基准 这些材料对抗强大的生物材料疫苗载体，以及临床相关的佐剂。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 两极分化免疫，为支持更合理的疫苗设计策略提供了新的见解。

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.