Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

产品说明：为了设计用于组织修复、细胞递送或治疗递送等应用的生物材料，处理免疫系统的流行方法一直是避免免疫系统。然而，随着新型生物材料和组合产品越来越多地含有蛋白质、肽和细胞，完全避免适应性免疫反应变得越来越具有挑战性。有一种方法来塑造，或“复制”这种反应到促进愈合的表型将大大加快这些有前途的新技术的临床转化。然而，实现这一目标的设计原则目前还处于起步阶段，这是由于缺乏可以系统地调整以引发各种适应性免疫表型（包括Th 2与Th 1极化）的生物材料平台。在这个项目中，我们将通过设计新型纳米纤维和水凝胶来解决这些挑战，这些纳米纤维和水凝胶来自自组装肽和蛋白质，这些肽和蛋白质对表位含量、多种T细胞极化细胞因子的精确比例及其在体内的持久性具有模块化控制。我们将利用这些材料， 测试中心假设，即引发短期、非炎症、Th 2极化免疫应答的材料将促进生物材料周围的促愈合环境。我们之前已经在这项工作中迈出了第一步，设计了新型的自辅助肽自组装体，这些肽在组织缺损中是非炎症性的并且耐受良好。为了使这些材料向Th 2或Th 1表型转化，并了解极化如何影响愈合，我们将开发一种新的自组装技术，即尾蛋白。尾蛋白可以被诱导自组装成纳米纤维和凝胶，其中含有精确控制量的多种不同的蛋白质。为了抑制T细胞应答并将它们特异性地导向材料，T细胞极化细胞因子（IL-、IL-10、IFN、IL-2）的尾衍生物将与限定的T细胞和B细胞表位共组装。为了控制材料的持久性和降解，我们将开发易水解的自组装缩肽，在酰胺骨架的目标位置具有酯键。将使用抗体同种型、组织学、ELISPOT和过继转移实验在小鼠模型中测量免疫应答。在全层切除皮肤伤口中，材料将被系统地工程化以通过适应性免疫系统促进愈合，并且Th 1/Th 2 T细胞极化的独立作用将通过在愈合过程中的几个时间点消耗T细胞来确定。这项工作将利用一个积极合作的多学科研究团队，他们在生物材料、免疫学、Th 1/Th 2极化和重建手术方面具有专业知识。所获得的知识不仅将为组织修复提供关键的新材料，还将阐明为含有蛋白质、肽和细胞的下一代设备引发富有成效的适应性免疫反应的设计原则。

DESCRIPTION: To design biomaterials for applications such as tissue repair, cell delivery, or therapeutic delivery, the prevailing approach for dealing with the immune system has been to avoid it. However, as newer classes of biomaterials and combination products increasingly contain proteins, peptides, and cells, it is becoming challenging to avoid adaptive immune responses entirely. Having a way to shape, or "polarize" such responses into phenotypes that promote healing would greatly accelerate the clinical translation of these promising new technologies. However, design principles for accomplishing this are currently in their infancy, owing to a lack of biomaterials platforms that can be systematically adjusted to elicit various adaptive immune phenotypes, including Th2 versus Th1 polarization. In this project we will address these challenges by designing novel nanofibers and hydrogels from self-assembling peptides and proteins that have modular control over epitope content, the precise ratios of multiple T cell-polarizing cytokines, and their persistence in vivo. We will use these materials to test the central hypothesis that materials eliciting short-duration, non- inflammatory, Th2-polarized immune responses will promote a pro-healing environment surrounding the biomaterial. We have previously taken the first step in this work by designing novel self-adjuvanting peptide self-assemblies that are non-inflammatory and well tolerated in tissue defects. To polarize these materials towards Th2 or Th1 phenotypes, and to understand how polarization affects healing, we will develop a new self-assembling technology, ¿-tail proteins. ¿-tail proteins can be induced to self-assemble into nanofibers and gels containing precisely controlled amounts of multiple different proteins of choice. To polarize T cell responses and direct them specifically against the material, tail derivatives of T cell polarizing cytokines (IL-, IL-10, IFN, IL-2) will be co-assembled with defined T cell and B cell epitopes. To control persistence and degradation of the materials, we will develop hydrolytically susceptible self-assembling depsipeptides, with ester bonds at targeted locations in the amide backbone. Immune responses will be measured in mouse models using antibody isotyping, histology, ELISPOT, and adoptive transfer experiments. In full- thickness excisional dermal wounds, the materials will be systematically engineered to facilitate healing via the adaptive immune system, and the independent role of Th1/Th2 T cell polarization will be determined by depleting T cells at several time points during the healing process. This work will take advantage of an actively collaborating multidisciplinary team of investigators with expertise in biomaterials, immunology, Th1/Th2 polarization, and reconstructive surgery. The knowledge gained will not only provide critical new materials for tissue repair but also clarify design principles for eliciting productiv adaptive immune responses for next-generation devices containing proteins, peptides, and cells.