Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives.
Targeting Regulatory T Cells for Transplant Tolerance: New Insights and Future Perspectives.
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针对移植耐受的调节性 T 细胞：新见解和未来前景。
DOI：
10.1159/000490703
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Gong,Rujun
中科院分区：
文献类型：
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作者：
Shaban,Eman;Bayliss,George;Malhotra,DeepakK;Shemin,Douglas;Wang,LiJuan;Gohh,Reginald;Dworkin,LanceD;Gong,Rujun
背景：器官移植被认为是终末期器官疾病的最终治疗方法。虽然药物免疫抑制是延长移植物存活的主要治疗策略，但长期使用免疫抑制药物会带来器官毒性、恶性肿瘤、严重的机会性感染和糖尿病的风险。在实体器官移植中，促进受体耐受性的疗法能够通过消除长期免疫抑制的需要来改善患者的预后。摘要：建立对同种异体移植物的耐受性已经成为一个深入研究的领域，并将成为临床实践中理想的治疗方法。T细胞的一个亚群自然地进行免疫调节的发现，导致了对其在移植免疫发病机制中的作用的进一步研究。有证据表明，调节性T细胞（Tregs）从根本上参与了促进同种异体移植物耐受。表征Tregs特异性标记的努力虽然具有挑战性，但已经确定Foxp3基因表达是促进Tregs耐受性诱导特征的关键步骤。许多方法，包括那些基于靶向糖原合成酶激酶3β信号通路或激活黑素皮质素能通路的方法，已经被测试为促进Treg谱系承诺和维持以及促进免疫耐受的方法。为了在临床实践中有效，Tregs必须是异体特异性的，并具有特定的表型，以避免抑制免疫系统的其他方面或增加恶性肿瘤或感染的风险。多项实验和临床研究已经证明了目前使用的免疫抑制剂对Tregs的免疫调节活性及其Foxp3表达状态的影响。包括表观遗传疗法在内的耐受性诱导Tregs的药理诱导正在兴起。关键信息：促进Treg功能和生存的治疗可能是实现移植患者免疫耐受的新策略。
Background:Organ transplantation is considered the ultimate therapy for end-stage organ disease. While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes. Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression.Summary:Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice. The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation. Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance. Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance-inducing features of Tregs. A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance. In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections. Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status. Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant.Key Messages:Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients.