Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States.
US Department of Veterans Affairs, Veterans Affairs Maryland Health Care System, Baltimore, MD, United States.
Front Immunol. 2023 Feb 6;14:1079910. doi: 10.3389/fimmu.2023.1079910. eCollection 2023.
Multiple sclerosis (MS) is an autoimmune disease that develops when dysfunctional autoreactive lymphocytes attack the myelin sheath in the central nervous system. There are no cures for MS, and existing treatments are associated with unwanted side effects. One approach for treating MS is presenting distinct immune signals (i.e., self-antigen and immunomodulatory cues) to innate and adaptive immune cells to engage multiple signaling pathways involved in MS. We previously developed immune polyelectrolyte multilayer (iPEM) complexes built through layer-by-layer deposition of self-antigen - myelin oligodendrocyte glycoprotein (MOG) - and toll-like receptor antagonist, GpG to treat MS. Here, glutaraldehyde-mediated stable cross-links were integrated into iPEMs to load multiple classes of therapeutics. These cross-linked iPEMs maintain their immunological features, including the ability of GpG to blunt toll-like-receptor 9 signaling and MOG to expand T cells expressing myelin-specific T cell receptors. Lastly, we show that these functional assemblies can be loaded with a critical class of drug - mTOR inhibitors - associated with inducing regulatory T cells. These studies demonstrate the ability to incorporate small molecule drugs in reinforced self-assembled immune signals juxtaposed at high densities. This precision technology contributes new technologies that could drive antigen-specific immune response by simultaneously modulating innate and adaptive immunity.
多发性硬化症（MS）是一种自身免疫性疾病，当功能失调的自身反应性淋巴细胞攻击中枢神经系统的髓鞘时就会发生。目前尚无治愈多发性硬化症的方法，现有的治疗方法都伴随着不良反应。治疗多发性硬化症的一种方法是向先天和适应性免疫细胞呈现独特的免疫信号（即自身抗原和免疫调节线索），以参与多发性硬化症相关的多个信号通路。我们之前开发了免疫聚电解质多层（iPEM）复合物，通过层层沉积自身抗原-髓鞘少突胶质细胞糖蛋白（MOG）-和 Toll 样受体拮抗剂 GpG 来治疗多发性硬化症。在这里，戊二醛介导的稳定交联被整合到 iPEM 中以加载多种治疗药物。这些交联的 iPEM 保持其免疫特性，包括 GpG 阻断 Toll 样受体 9 信号和 MOG 扩展表达髓鞘特异性 T 细胞受体的 T 细胞的能力。最后，我们表明这些功能组件可以加载一类关键药物 - mTOR 抑制剂 - 与诱导调节性 T 细胞有关。这些研究表明能够在高密度并列的强化自身组装免疫信号中掺入小分子药物。这项精确技术提供了新的技术，可通过同时调节先天和适应性免疫来驱动抗原特异性免疫反应。
