免疫调节纳米颗粒使联合疗法增强类风湿关节炎的疾病预防和耀斑控制

IF 10.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Wade T. Johnson, , , Elizabeth L. Wilkinson, , , Neha Iyer, , , Maksim Dolmat, , , Miriam Bollmann, , , Nour Dada, , , Xiaofu Wei, , , Shen Yang, , , Tiffany Zhang, , , Grace Yoo, , , Marianne Bernardo, , , Madison Price, , , Elizabeth Frame, , , Mariko Ishimori, , , Jon T. Giles, , , Wei Wang, , , Mattias N.D. Svensson, , , Nunzio Bottini*, , and , Nisarg J. Shah*, 
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引用次数: 0

摘要

改善疾病的抗风湿药物(DMARDs)极大地改善了类风湿性关节炎(RA)的治疗,但预防疾病发作和复发的策略仍然有限。虽然阿巴接受(CTLA-4 IgG)可以延缓RA发作,皮质类固醇用于控制耀斑,但益处是暂时的。我们报道,将标准护理治疗与局部给药的免疫调节剂(称为Agg-CLNP)相结合,可以增强疾病预防和缓解耀斑。Agg-CLNP由聚合物纳米颗粒与免疫优势聚集肽结合并包裹骨化三醇组成。这些纳米颗粒经过优化,可被关节炎关节近端淋巴结中的树突状细胞(DC)摄取。在体外,Agg-CLNP抑制来自健康和RA供者的人单核细胞来源DC的共刺激分子和HLA II类(HLA-2)表达,上调CTLA-4。在SKG小鼠(一种T细胞驱动的RA模型)中,Agg-CLNP与CTLA-4 IgG联合可协同延缓疾病发作并降低严重程度。在地塞米松(Dex)戒断型耀斑模型中,去Dex后Agg-CLNP治疗降低了耀斑严重程度,并保留了DC中的调节表型,同时抑制了局部致病性TH17细胞。淋巴结DC的下一代RNA测序显示Ctla4上调和其他与耀斑预防相关的免疫调节基因的变化。这些发现强调Agg-CLNP作为一种潜在的治疗策略来解决RA管理中关键的未满足的需求。Agg-CLNP是一种疾病调节剂,可调节免疫激活,有效抑制疾病发作和控制耀斑,为类风湿关节炎未满足的需求提供了潜在的解决方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Immunomodulatory Nanoparticles Enable Combination Therapies To Enhance Disease Prevention and Flare Control in Rheumatoid Arthritis

Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.

Agg-CLNP is a disease modifying agent which modulates immune activation and effectively suppresses disease onset and controls flares, providing a potential solution to unmet needs in rheumatoid arthritis.

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来源期刊
ACS Central Science
ACS Central Science Chemical Engineering-General Chemical Engineering
CiteScore
25.50
自引率
0.50%
发文量
194
审稿时长
10 weeks
期刊介绍: ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.
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