A New Immunosuppressive Molecule Emodin Induces both CD4(+)FoxP3(+) and CD8(+)CD122(+) Regulatory T Cells and Suppresses Murine Allograft Rejection.
A New Immunosuppressive Molecule Emodin Induces both CD4(+)FoxP3(+) and CD8(+)CD122(+) Regulatory T Cells and Suppresses Murine Allograft Rejection.
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一种新的免疫抑制分子大黄素诱导 cD4 FoxP3 和 cD8 cD122 调节性 T 细胞并抑制小鼠同种异体移植排斥
DOI：
10.3389/fimmu.2017.01519
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发表时间：
2017
影响因子：
7.3
通讯作者：
Dai Z
中科院分区：
文献类型：
--
作者：
Qiu F;Liu H;Liang CL;Nie GD;Dai Z
由于强烈的同种异体免疫反应，在没有任何常规免疫抑制治疗的情况下，同种异体移植物通常会被排斥。然而，持续的全身性免疫抑制可能会导致严重的副作用，包括肿瘤和感染。越来越多的证据表明，环孢素（CsA）这种临床上常用的免疫抑制剂，虽然能同时抑制同种异体移植物排斥反应，但会通过抑制调节性T细胞（Tregs）阻碍同种异体移植物的耐受性。因此，有必要寻找一种替代的免疫抑制药物，它能高效地保留Tregs，具有高抑制效率且低毒性。在本研究中，我们研究了大黄素（一种最初从某些天然植物中提取的蒽醌分子）在小鼠模型中延长移植物存活的能力，并探讨了其作用的细胞和分子机制。我们发现大黄素显著延长了皮肤同种异体移植物的存活时间，并阻碍了同种异体移植物中CD3 + T细胞的浸润，同时伴随着受体小鼠中CD4 + Foxp3 +和CD8 + CD122 + Treg的频率和数量增加，但效应CD8 + CD44highCD62Llow T细胞减少。大黄素还抑制了体内效应CD8 + T细胞的增殖。然而，来自大黄素处理受体的CD4 + CD25 + Tregs（而非CD8 + CD122 + Tregs）在抑制同种异体移植物排斥方面比从对照受体中分离出的更有效，这表明大黄素还增强了CD4 + CD25 + Tregs的抑制功能。有趣的是，清除CD25 + Tregs在很大程度上逆转了大黄素延长的皮肤同种异体移植物存活时间，而清除CD122 + Tregs仅部分消除了相同的同种异体移植物存活时间。此外，我们发现大黄素阻碍了树突状细胞（DC）的成熟，并减少了移植后的同种抗体产生。最后，我们证明大黄素抑制了T细胞的体外增殖，并阻断了它们的mTOR信号通路。因此，大黄素可能是一种新型的mTOR抑制剂，它通过诱导CD4 + FoxP3 +和CD8 + CD122 + Tregs、抑制同种抗体产生以及阻碍DC成熟来抑制同种异体免疫。因此，大黄素是一种新出现的免疫抑制剂，未来可用于临床移植。
Due to vigorous alloimmunity, an allograft is usually rejected without any conventional immunosuppressive treatment. However, continuous global immunosuppression may cause severe side effects, including tumors and infections. Mounting evidence has shown that cyclosporine (CsA), a common immunosuppressant used in clinic, impedes allograft tolerance by dampening regulatory T cells (Tregs), although it inhibits allograft rejection at the same time. Therefore, it is necessary to seek an alternative immunosuppressive drug that spares Tregs with high efficiency in suppression but low toxicity. In this study, we investigated the capacity of emodin, an anthraquinone molecule originally extracted from certain natural plants, to prolong transplant survival in a mouse model and explored the cellular and molecular mechanisms underlying its action. We found that emodin significantly extended skin allograft survival and hindered CD3+ T cell infiltration in the allograft, accompanied by an increase in CD4+Foxp3+ and CD8+CD122+ Treg frequencies and numbers but a reduction in effector CD8+CD44highCD62Llow T cells in recipient mice. Emodin also inhibited effector CD8+ T cells proliferation in vivo. However, CD4+CD25+, but not CD8+CD122+, Tregs derived from emodin-treated recipients were more potent in suppression of allograft rejection than those isolated from control recipients, suggesting that emodin also enhances the suppressive function of CD4+CD25+ Tregs. Interestingly, depleting CD25+ Tregs largely reversed skin allograft survival prolonged by emodin while depleting CD122+ Tregs only partially abrogated the same allograft survival. Furthermore, we found that emodin hindered dendritic cell (DC) maturation and reduced alloantibody production posttransplantation. Finally, we demonstrated that emodin inhibited in vitro proliferation of T cells and blocked their mTOR signaling as well. Therefore, emodin may be a novel mTOR inhibitor that suppresses alloimmunity by inducing both CD4+FoxP3+ and CD8+CD122+ Tregs, suppressing alloantibody production, and hindering DC maturation. Thus, emodin is a newly emerging immunosuppressant and could be utilized in clinical transplantation in the future.
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DOI：
10.4049/jimmunol.1003812
发表时间：
2011-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Molloy MJ;Zhang W;Usherwood EJ
通讯作者：
Usherwood EJ
大黄素抑制大鼠同种异体肝移植后急性排斥反应的作用
影响因子：
2.9
作者：
Lin Sheng-zhang;Tong Hong-fei;Zheng Shu-sen
通讯作者：
Zheng Shu-sen
影响因子：
8.8
作者：
Gao, W.;Lu, Y.;Strom, T. B.
通讯作者：
Strom, T. B.
影响因子：
8.8
作者：
Dai, Z.;Zhang, S.;Li, X. C.
通讯作者：
Li, X. C.
CD8( )CD122( ) T 细胞：具有中央记忆细胞表型的新兴调节因子
影响因子：
7.3
作者：
Liu J;Chen D;Nie GD;Dai Z
通讯作者：
Dai Z