通过化学定义系统在体内生成的人 CD1c+ 调节性 B 细胞可抑制免疫反应并缓解移植物抗宿主疾病。

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-26 DOI:10.1016/j.ymthe.2024.10.026
Yingying Bao, Jialing Liu, Zhishan Li, Yueming Sun, Junhua Chen, Yuanchen Ma, Gang Li, Tao Wang, Huanyi Liu, Xiaoran Zhang, Rong Yan, Zhenxia Yao, Xiaolu Guo, Rui Fang, Jianqi Feng, Wenjie Xia, Andy Peng Xiang, Xiaoyong Chen
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引用次数: 0

摘要

IL-10+调节性B细胞(Bregs)在治疗移植物抗宿主疾病(GVHD)--一种威胁造血干细胞移植后生命的并发症--方面显示出巨大的前景。然而,由于缺乏独特的特异性标志物和触发促炎细胞因子的表达,在体外获得高质量的人类IL-10+ Bregs仍是一项挑战。在这里,我们通过揭示间充质基质细胞(MSCs)诱导Bregs的关键信号通路,首次建立了基于间充质基质细胞和GSK-3β阻断(CHIR-99021)的高效Bregs诱导系统,该系统具有强大的诱导IL-10+ Bregs的能力,同时抑制TNF-α的表达。此外,这些 Bregs 群体可被 CD1c+ 识别和富集。从机制上讲,间充质干细胞通过 PKA 介导的 cAMP 反应元件结合蛋白(CREB)磷酸化诱导 Bregs 的扩增。因此,我们开发了一种化学定义的诱导方案,即用 PKA-CREB 激动剂代替间充质干细胞,也能有效诱导 CD1c+ Bregs,同时降低 TNF-α 的表达。重要的是,诱导的 CD1c+ Bregs 能抑制 PBMC 的增殖和 T 细胞的炎性细胞因子分泌。将诱导的 CD1c+ Bregs 移植到人源化小鼠 GVHD 模型中,可有效缓解 GVHD。总之,我们建立了一种高效的人 Bregs 体外诱导系统,这对开发基于 Bregs 的新型 GVHD 治疗方法具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ex vivo-generated human CD1c+ regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease.

IL-10+ regulatory B cells (Bregs) show great promise in treating graft-versus-host disease (GVHD), a life-threatening complication of post-hematopoietic stem cell transplantation. However, obtaining high-quality human IL-10+ Bregs in vitro remains a challenge due to the lack of unique specific markers and the triggering of pro-inflammatory cytokine expression. Here, by uncovering the critical signaling pathways in Breg induction by mesenchymal stromal cells (MSCs), we first established an efficient Breg induction system based on MSCs and GSK-3β blockage (CHIR-99021), which had a robust capacity to induce IL-10+ Bregs while suppressing tumor necrosis factor α (TNF-α) expression. Furthermore, these Breg populations could be identified and enriched by CD1c+. Mechanistically, MSCs induced the expansion of Bregs through the PKA-mediated phosphorylation of cAMP response element-binding protein (CREB). Thus, we developed a chemically defined inducing protocol by PKA-CREB agonist, instead of MSCs, which can also effectively induce CD1c+ Bregs with lower TNF-α expression. Importantly, induced CD1c+ Bregs suppressed the proliferation of peripheral blood mononuclear cells and the inflammatory cytokine secretion of T cells. When adoptively transferred into a humanized mouse model of GVHD, induced CD1c+ Bregs effectively alleviated GVHD. Overall, we established an efficient ex vivo induction system for human Bregs, which has implications for developing novel Bregs-based therapies for GVHD.

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来源期刊
Molecular Therapy
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.
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