Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

描述：为了设计用于组织修复、细胞输送或治疗性输送等应用的生物材料，处理免疫系统的主流方法一直是避免它。然而，随着较新类别的生物材料和组合产品中越来越多地含有蛋白质、多肽和细胞，完全避免适应性免疫反应变得越来越具有挑战性。有办法将这些反应塑造或“极化”成促进愈合的表型，将极大地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初级阶段，因为缺乏可以系统调整以诱导各种适应性免疫表型的生物材料平台，包括Th2与Th1极化。在这个项目中，我们将通过自组装多肽和蛋白质设计新型纳米纤维和水凝胶来应对这些挑战，这些多肽和蛋白质具有对表位含量、多种T细胞极化细胞因子的精确比例以及它们在体内的持久性的模块化控制。我们将使用这些材料来 测试核心假设，即激发短期、非炎症性、Th2极化的免疫反应的材料将促进生物材料周围有利于愈合的环境。我们之前已经在这项工作中迈出了第一步，设计了新型的自我调节多肽自组装，这些自我调整多肽是非炎症性的，在组织缺损中具有良好的耐受性。为了将这些材料极化成Th2或Th1表型，并了解极化是如何影响愈合的，我们将开发一种新的自组装技术-尾巴蛋白。尾巴蛋白可以被诱导自组装成纳米纤维和凝胶，其中包含精确控制数量的多种不同蛋白质的选择。为了极化T细胞反应并针对材料特异性地定向它们，T细胞极化细胞因子(IL-、IL-10、干扰素、IL-2)的尾部衍生物将与确定的T细胞和B细胞表位共同组装。为了控制材料的持久性和降解性，我们将开发易水解的自组装脱脂肽，在酰胺主干的目标位置具有酯键。免疫反应将通过抗体同型、组织学、ELISPOT和过继转移实验在小鼠模型中进行测量。在全层切除真皮创伤中，材料将被系统地设计成通过适应性免疫系统促进愈合，而Th1/Th2 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。这项工作将利用一支积极合作的多学科研究团队，他们拥有生物材料、免疫学、Th1/Th2极化和重建外科方面的专业知识。所获得的知识不仅将为组织修复提供关键的新材料，还将阐明为包含蛋白质、多肽和细胞的下一代设备激发高效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.