Modulating the conformation of the TIR domain by a neoteric MyD88 inhibitor leads to the separation of GVHD from GVT
Modulating the conformation of the TIR domain by a neoteric MyD88 inhibitor leads to the separation of GVHD from GVT
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通过近代 MyD88 抑制剂调节 TIR 结构域的构象导致 GVHD 与 GVT 分离
DOI：
10.1080/10428194.2018.1537487
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发表时间：
2018-12
影响因子：
2.6
通讯作者：
Zhou P
中科院分区：
文献类型：
--
作者：
Xing S;Zhang X;Huang X;Xie L;Jiang F;Zhou P
移植物抗宿主病（GVHD）仍然是异基因骨髓移植（BMT）后最难治愈的并发症。髓样分化因子88（MyD 88）是一种重要参与Toll样受体（TLR）信号传导途径的衔接分子。MyD 88和TLR的Toll/IL-1受体（TIR）结构域是负责通过直接或间接的TIR-TIR相互作用进行分选和信号传导的干扰模块，其可以促进GVHD进展的所有阶段。在这里，我们描述了新型MyD 88抑制剂TJ-M2010-5的机制，以及在完全MHC错配的小鼠模型中发现其在GVHD和移植物抗肿瘤（GVT）效应背景下的免疫抑制特性。TJ-M2010-5通过其预测的DD环、BB环和Poc位点潜在地中断TIR结构域的构象，并以剂量依赖性方式抑制MyD 88的同源二聚化、LPS刺激的树突状细胞活化和供体同种异体T细胞增殖的引发。口服TJ-M2010-5可改善炎症环境，减少凋亡细胞数量，增加GVHD靶器官的组织修复，并抑制致死性GVHD。此外，TJ-M2010-5对GVHD的保护没有消除针对骨髓瘤细胞系SP2/0的GVT效应。我们的数据定义了作用机制，并为TJ-M2010 -5预防GVHD的潜在临床用途提供了新的见解。
Graft-versus-host disease (GVHD) remains the least curable complication after allogeneic bone marrow transplantation (BMT). Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critically involved in the toll-like receptor (TLR) signaling pathway. The Toll/IL-1 receptor (TIR) domains of MyD88 and TLR are interactional modules responsible for sorting and signaling via direct or indirect TIR-TIR interactions, which can contribute to all phases of GVHD progression. Here, we describe the mechanisms of the novel MyD88 inhibitor, TJ-M2010-5, and the discovery of its immunosuppressive properties in the context of GVHD and the graft-versus-tumor (GVT) effect in a fully MHC-mismatched murine model. TJ-M2010-5 potentially interrupted the conformation of the TIR domain through its predicted DD loops, BB loops, and Poc site, and inhibited the homodimerization of MyD88, the LPS-stimulated activation of dendritic cells, and the priming of donor allogeneic T cell proliferation in a dose-dependent manner. Oral administration of TJ-M2010-5 ameliorated the inflammatory environment, decreased the number of apoptotic cells, increased tissue repair in GVHD target organs, and suppressed lethal GVHD. Further, protection against GVHD by TJ-M2010-5 did not abrogate a GVT effect against SP2/0, a myeloma cell line. Our data define the mechanisms of actions and provide novel insight into the potential clinical uses of TJ-M2010-5 for GVHD prevention.
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影响因子：
4.6
作者：
Zhang LM;Liu JH;Xue CB;Li MQ;Xing S;Zhang X;He WT;Jiang FC;Lu X;Zhou P
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通讯作者：
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Ji-Young Lim;Young Kwan Lee;S. Lee;J. Ju;K. Eom;Yun Ju Kim;Nak-Gyun Chung;Dae-Chul Jeong;G. Park;Choi Ey;Chang-Ki Min
DOI：
10.1681/asn.2012010052
发表时间：
2012-10
期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
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作者：
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通讯作者：
Hui-ling Wu;Gerda A. Noordmans;Maya R. O’Brien;Jin Ma;C. Zhao;Geoff Zhang;Tony K Kwan;S. Alexander-S.-Alex
影响因子：
5.5
作者：
Loiarro, Maria;Capolunghi, Federica;Sette, Claudio
通讯作者：
Sette, Claudio