《生命科学》 2026, 38(4): 736-752
耐受性树突状细胞在多发性硬化治疗中的作用：从机制到临床转化
摘 要：
多发性硬化（MS）是一种以中枢神经系统脱髓鞘为特征的慢性自身免疫性疾病，其核心病理机制为自身反应性T细胞穿越血脑屏障，攻击髓鞘抗原并引发持续性炎症反应。树突状细胞（DCs）作为最专业的抗原提呈细胞，在启动、维持和调控自身免疫反应中发挥关键作用。传统DCs活化后可促进辅助性T细胞1型（Th1）/Th17细胞介导的炎症反应，从而参与MS的发生与进展。近年来，耐受性树突状细胞（tolDCs）因其能够诱导抗原特异性免疫耐受、抑制自身反应性淋巴细胞活化、促进调节性T细胞生成等特征，成为MS治疗研究的新兴方向。本文系统综述tolDCs的生物学特征、诱导策略及分子机制，重点总结其在实验性自身免疫性脑脊髓炎模型及临床研究中的应用进展，进一步分析tolDCs在抗原特异性免疫耐受中的关键作用及其临床转化面临的挑战，并探讨其向精准免疫治疗策略发展的潜在方向。
通讯作者：王闻雅 , Email:wwya03378@btch.edu.cn
Abstract:
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory demyelination and neurodegeneration within the central nervous system. Its pathogenesis is primarily driven by autoreactive T cells that infiltrate the blood-brain barrier and initiate immune-mediated damage against myelin antigens. Although current disease-modifying therapy can delay disease progression, they largely rely on non-specific immunosuppression and are associated with increased risks of infection and malignancy, while failing to achieve durable immune tolerance or functional cure. Therefore, the development of antigen-specific immunotherapies capable of restoring immune homeostasis has become a critical unmet need. Tolerogenic dendritic cells (tolDCs) have emerged as a promising strategy for inducing antigen-specific immune tolerance in MS. As key regulators bridging innate and adaptive immunity, dendritic cells exhibit functional plasticity, enabling them to either promote inflammatory responses or induce immune tolerance depending on environmental cues. tolDCs are characterized by low expression of co-stimulatory molecules, high expression of inhibitory receptors, and enhanced secretion of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-β. These cells suppress autoreactive T cell activation, promote regulatory T cells and regulatory B cells differentiation, and reshape immune responses toward a tolerogenic state. This review systematically summarizes the biological features, induction strategies, and molecular mechanisms underlying tolDC-mediated immune tolerance. We highlight multi-layered regulatory pathways, including immunosuppressive signaling (e.g., programmed death-1/programmed death ligand-1 and cytotoxic T lymphocyte antigen-4), metabolic reprogramming, transcriptional and epigenetic networks, and apoptosis-mediated deletion of pathogenic T cells. In addition, we provide an overview of current approaches for generating tolDCs, including pharmacological modulation, cytokine conditioning, genetic engineering, and in vivo targeting strategies using nanoparticles or receptorspecific delivery systems. Evidence from experimental autoimmune encephalomyelitis models and early-phase clinical trials demonstrates that tolDC-based therapies are safe, feasible, and capable of inducing antigen-specific immune regulation. Despite these advances, several challenges remain for clinical translation, including the heterogeneity and stability of tolDCs, lack of standardized manufacturing protocols, patient-specific antigen selection, and the need for robust immune monitoring biomarkers. Future directions should focus on integrating multi-omics technologies, precision antigen identification, and bioengineering approaches to enhance the specificity, stability, and scalability of tolDC-based therapies. Ultimately, tolDCs represent a transformative platform shifting from broad immunosuppression toward precise immune reprogramming, offering new therapeutic opportunities for MS and other autoimmune diseases.
Communication Author：WANG Wen-Ya , Email:wwya03378@btch.edu.cn
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