Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells
Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells
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DOI：
10.1016/j.cellimm.2018.09.008
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发表时间：
2019-05-01
影响因子：
4.3
通讯作者：
Prabhakar, Bellur S.
中科院分区：
文献类型：
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作者：
Kumar, Prabhakaran;Saini, Shikha;Prabhakar, Bellur S.
自身耐受，即对自身组织/抗原无反应的状态，通过中枢和外周耐受机制维持，这些机制的破坏导致自身免疫性疾病。Foxp 3+调节性T细胞（Foxp 3 + T-regulatory cells，TCRs）在抑制针对自身抗原的自身免疫反应中发挥重要作用，从而调节自身耐受。天然的TCRs基于其对自身抗原的较高TCR亲和力在胸腺中分化，并迁移到外周，在外周它们维持外周耐受性。此外，诱导的胸腺外分化可以发生在外周，这可以控制炎症条件下的突然免疫应答。发现Treg细胞数量和/或功能的缺陷与几种实验模型和人类自身免疫性疾病中自身免疫性疾病的发展相关。此外，已显示TcG的增强在临床前模型中治疗自身免疫中是有益的，并且基于Treg的细胞疗法已在临床试验中显示出初步前景。然而，新兴的研究已经确定了一个不稳定的亚群的TCLs表达促炎细胞因子下的稳态和自身免疫条件下，以及在离体培养。此外，Treg细胞疗法的临床转化受到限制的阻碍，例如缺乏用于选择性扩增Treg的更容易的方法以及与细胞分选、离体扩增和输注离体扩增的Treg所需的GMP设施相关的更高成本。在这里，我们讨论了调节Treg分化，Foxp 3表达和谱系稳定性的分子机制的最新进展，TcR在预防各种自身免疫性疾病中的作用，并严格审查其治疗人类自身免疫性疾病的临床效用。
Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.