Freire Haddad Helena, Roe Emily F, Xie Fu Vinicius, Curvino Elizabeth J, Collier Joel H
Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
Adv Healthc Mater. 2025 Jan;14(1):e2402546. doi: 10.1002/adhm.202402546. Epub 2024 Oct 30.
The anaphylatoxins C3a and C5a are products of the complement cascade that play important and interrelated roles in health and disease. Both are potential targets for anti-inflammatory active immunotherapies in which a patient's own immune system is stimulated to produce therapeutic immune responses against problematic self-molecules. However, the complex and time-dependent interrelations between the two molecules make dual targeting challenging. To investigate a dual-target active immunotherapy against C3a and C5a and to systematically study the effect of varied degrees of responses against both targets, the study employed self-assembled peptide immunogens capable of displaying a broad range of epitope compositions and Design-of-Experiments (DoE) approaches. Peptide nanofibers contained B-cell epitopes of C3a and C5a in defined quantities, and intranasal immunization raised systemic and mucosal immunity against each target. In a lipopolysaccharide-induced model of sepsis, increasing anti-C5a responses are protective, whereas increasing anti-C3a responses are detrimental, and survival rates are negatively correlated with anti-C3a/anti-C5a IgG titer ratio. This work highlights the interplay between the two molecules by making use of a modular, defined, and easily adjusted biomaterial-based active immunotherapy platform.
过敏毒素C3a和C5a是补体级联反应的产物，在健康和疾病中发挥着重要且相互关联的作用。二者都是抗炎活性免疫疗法的潜在靶点，这类疗法会刺激患者自身的免疫系统产生针对有问题的自身分子的治疗性免疫反应。然而，这两种分子之间复杂且依赖时间的相互关系使得双靶点治疗颇具挑战性。为了研究针对C3a和C5a的双靶点活性免疫疗法，并系统地研究针对两个靶点的不同程度反应的效果，该研究采用了能够展示广泛表位组成的自组装肽免疫原和实验设计（DoE）方法。肽纳米纤维含有定量的C3a和C5a的B细胞表位，鼻内免疫可增强针对每个靶点的全身和黏膜免疫。在脂多糖诱导的脓毒症模型中，抗C5a反应增强具有保护作用，而抗C3a反应增强则有害，生存率与抗C3a/抗C5a IgG滴度比呈负相关。这项工作通过利用基于模块化、明确且易于调整的生物材料的活性免疫疗法平台，突出了这两种分子之间的相互作用。
