Department of Biomedical Engineering, Duke University, Durham, NC, 27708, United States.
Department of Biomedical Engineering, Duke University, Durham, NC, 27708, United States.
Biomaterials. 2021 Jun;273:120825. doi: 10.1016/j.biomaterials.2021.120825. Epub 2021 Apr 15.
Biomaterials capable of inducing immune responses with minimal associated inflammation are of interest in applications ranging from tissue repair to vaccines. Here we report the design of self-assembling randomized polypeptide nanomaterials inspired by glatiramoids, an immunomodulatory class of linear random copolymers. We hypothesized that peptide self-assemblies bearing similar randomized polypeptides would similarly raise responses skewed toward Type 2 immunity and T2 T-cell responses, additionally strengthening responses to co-assembled peptide epitopes in the absence of adjuvant. We developed a method for synthesizing self-assembling peptides terminated with libraries of randomized polypeptides (termed KEYA) with good batch-to-batch reproducibility. These peptides formed regular nanofibers and raised strong antibody responses without adjuvants. KEYA modifications dramatically improved uptake of peptide nanofibers in vitro by antigen presenting cells, and served as strong B-cell and T-cell epitopes in vivo, enhancing immune responses against epitopes relevant to influenza and chronic inflammation while inducing a KEYA-specific Type 2/T2/IL-4 phenotype. KEYA modifications also increased IL-4 production by T cells, extended the residence time of nanofibers, induced no measurable swelling in footpad injections, and decreased overall T cell expansion compared to unmodified nanofibers, further suggesting a T2 T-cell response with minimal inflammation. Collectively, this work introduces a biomaterial capable of raising strong Type 2/T2/IL-4 immune responses, with potential applications ranging from vaccination to tissue repair.
具有最小炎症相关免疫原性的生物材料在从组织修复到疫苗等应用中具有吸引力。在这里，我们报告了受免疫调节线性无规共聚物类 glatiramoids 启发的自组装无规多肽纳米材料的设计。我们假设具有类似无规多肽的肽自组装体将类似地引起偏向 2 型免疫和 T2 型 T 细胞反应的反应，并且在没有佐剂的情况下还可以增强对共同组装的肽表位的反应。我们开发了一种用于合成带有无规多肽库（称为 KEYA）的自组装肽的方法，该方法具有良好的批间重现性。这些肽形成规则的纳米纤维，在没有佐剂的情况下可引发强烈的抗体反应。 KEYA 修饰极大地提高了抗原呈递细胞体外对肽纳米纤维的摄取，并且在体内作为强 B 细胞和 T 细胞表位，增强了对流感和慢性炎症相关表位的免疫反应，同时诱导 KEYA 特异性 2 型/T2/IL-4 表型。 KEYA 修饰还增加了 T 细胞的 IL-4 产生，延长了纳米纤维的停留时间，在足垫注射中未引起可测量的肿胀，与未修饰的纳米纤维相比，总体 T 细胞扩增减少，进一步表明具有最小炎症的 2 型 T 细胞反应。总的来说，这项工作介绍了一种能够引发强烈 2 型/T2/IL-4 免疫反应的生物材料，其潜在应用范围从疫苗接种到组织修复。
