Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

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，处理免疫系统的主要方法是避免使用它。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、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。有一种方法来塑造或“极化”这种反应，使其成为促进愈合的表型，将极大地加速这些有前途的新技术的临床转化。然而，由于缺乏可以系统调整以引发各种适应性免疫表型（包括Th2与Th1极化）的生物材料平台，实现这一目标的设计原则目前尚处于起步阶段。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，这些肽和蛋白质具有模块化控制表位内容，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。我们将使用这些材料来

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.