A novel tolerogenic antigen-specific vaccine induces VISTA-enriched regulatory T cells and protects against arthritis in DRB1*04:01 mice.

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-04-24 DOI:10.1016/j.ymthe.2025.04.034

Laura Romero-Castillo,Rajan Kumar Pandey,Bingze Xu,Christian M Beusch,Ana Oliveira-Coelho,Kejsi Zeqiraj,Carolin Svensson,Zhongwei Xu,Huqiao Luo,Outi Sareila,Pierre Sabatier,Changrong Ge,Lei Cheng,Vilma Urbonaviciute,Alexander Krämer,Cecilia Lindgren,Sabrina Haag,Johan Viljanen,Roman A Zubarev,Jan Kihlberg,Anna Linusson,Harald Burkhardt,Rikard Holmdahl

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引用次数: 0

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, cartilage damage and bone erosion. Despite improvements with the introduction of biological disease-modifying anti-rheumatic drugs (DMARDs), RA remains an incurable life-lasting disease. Advancements in peptide-based vaccination may open new avenues for treating autoimmune diseases, including RA, by inducing immune tolerance while maintaining normal immune function. Previously we have already demonstrated the efficacy of a potent vaccine against RA, consisting of the mouse major histocompatibility complex class II (Aq) protein bound to the immunodominant type II collagen peptide COL2259-273, which needed to be galactosylated at position 264. To translate the vaccine to humans and to further enhance vaccine efficacy, we modified the glycine residue at position 265 and conjugated it with the human DRB1*04:01 molecule. Remarkably, this modified vaccine (named DR4-AL179) provided robust effectiveness in suppressing arthritis in DRB1*04:01-expressing mice without the need for galactosylation at position 264. DR4-AL179 vaccination induces tolerance involving multiple immunoregulatory pathways, including the activation of VISTA-positive nonconventional regulatory T cells, which contribute to a potent suppressive response preventing arthritis development in mice. This modified RA vaccine offers a novel therapeutic potential for human autoimmune diseases.

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一种新的耐受性抗原特异性疫苗诱导富含vista的调节性T细胞，并对DRB1*04:01小鼠的关节炎有保护作用。

类风湿性关节炎（RA）是一种以关节炎症、软骨损伤和骨侵蚀为特征的慢性自身免疫性疾病。尽管随着生物疾病改善抗风湿药物（DMARDs）的引入，RA仍然是一种无法治愈的终身疾病。基于肽的疫苗接种的进展可能通过诱导免疫耐受同时维持正常的免疫功能，为治疗自身免疫性疾病（包括类风湿性关节炎）开辟新的途径。先前我们已经证明了一种有效的抗RA疫苗的有效性，该疫苗由小鼠主要组织相容性复合体II类（Aq）蛋白与免疫优势型II型胶原肽COL2259-273结合组成，该蛋白需要在264位半乳糖化。为了将疫苗转译到人体内并进一步提高疫苗的效力，我们对位于265位的甘氨酸残基进行修饰，并将其与人DRB1*04:01分子偶联。值得注意的是，这种改良疫苗（命名为DR4-AL179）在表达DRB1*04:01的小鼠中提供了强大的抑制关节炎的有效性，而不需要在264位进行半乳糖基化。DR4-AL179疫苗接种诱导涉及多种免疫调节途径的耐受性，包括vista阳性非常规调节性T细胞的激活，这有助于有效的抑制反应，防止小鼠关节炎的发展。这种改良的类风湿性关节炎疫苗为人类自身免疫性疾病提供了一种新的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.