Blockade of IL-6/IL-6R Signaling Attenuates Acute Antibody-Mediated Rejection in a Mouse Cardiac Transplantation Model.
Blockade of IL-6/IL-6R Signaling Attenuates Acute Antibody-Mediated Rejection in a Mouse Cardiac Transplantation Model.
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阻断 IL-6/IL-6R 信号传导可减轻小鼠心脏移植模型中抗体介导的急性排斥反应
DOI：
10.3389/fimmu.2021.778359
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发表时间：
2021
影响因子：
7.3
通讯作者：
Sun Q
中科院分区：
文献类型：
--
作者：
Ma M;Sun Q;Li X;Deng G;Zhang Y;Yang Z;Han F;Huang Z;Fang Y;Liao T;Sun Q
急性抗体介导的排斥反应(AAMR)是同种异体心脏移植功能障碍的重要原因，需要探索更有效的策略来改善同种异体心脏移植的预后。白介素6/白介素6R信号通路在免疫细胞的激活中起关键作用，包括B细胞、T细胞和巨噬细胞，这些细胞参与AAMR的发展。在本研究中，我们在小鼠模型上研究了IL-6/IL-6R信号通路阻断在预防AAMR中的作用。我们通过皮片预敏和环孢素A的加入，建立了小鼠心脏移植AAMR模型，并对其特点进行了分析。用Tocilizumab、抗IL-6R抗体和受体IL-6基因敲除阻断IL-6/IL-6R信号转导。我们证明，阻断IL-6/IL-6R信号显著减轻同种异体移植物损伤，提高存活率。进一步的机制研究表明，信号阻断减少了循环、脾和同种异体移植中的B细胞，从而抑制了供者特异性抗体的产生和补体的激活。此外，同种异体移植物中巨噬细胞、T细胞和促炎细胞因子的浸润也减少。总之，我们提供了一种高度实用的AAMR小鼠模型，并证明阻断IL-6/IL-6R信号可显著缓解AAMR，有望为临床治疗AAMR提供一种更好的选择。
Acute antibody-mediated rejection (AAMR) is an important cause of cardiac allograft dysfunction, and more effective strategies need to be explored to improve allograft prognosis. Interleukin (IL)-6/IL-6R signaling plays a key role in the activation of immune cells including B cells, T cells and macrophages, which participate in the progression of AAMR. In this study, we investigated the effect of IL-6/IL-6R signaling blockade on the prevention of AAMR in a mouse model. We established a mouse model of AAMR for cardiac transplantation via presensitization of skin grafts and addition of cyclosporin A, and sequentially analyzed its features. Tocilizumab, anti-IL-6R antibody, and recipient IL-6 knockout were used to block IL-6/IL-6R signaling. We demonstrated that blockade of IL-6/IL-6R signaling significantly attenuated allograft injury and improved survival. Further mechanistic research revealed that signaling blockade decreased B cells in circulation, spleens, and allografts, thus inhibiting donor-specific antibody production and complement activation. Moreover, macrophage, T cell, and pro-inflammatory cytokine infiltration in allografts was also reduced. Collectively, we provided a highly practical mouse model of AAMR and demonstrated that blockade of IL-6/IL-6R signaling markedly alleviated AAMR, which is expected to provide a superior option for the treatment of AAMR in clinic.
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影响因子：
168.9
作者：
Dhital, Kumud K.;Iyer, Arjun;Macdonald, Peter
通讯作者：
Macdonald, Peter
DOI：
10.1016/j.healun.2016.04.007
发表时间：
2016-09
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
--
作者：
Clerkin KJ;Restaino SW;Zorn E;Vasilescu ER;Marboe CC;Mancini DM
通讯作者：
Mancini DM
DOI：
10.4049/jimmunol.1100766
发表时间：
2011-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Booth AJ;Grabauskiene S;Wood SC;Lu G;Burrell BE;Bishop DK
通讯作者：
Bishop DK
DOI：
10.1111/j.1600-6143.2009.02826.x
发表时间：
2010-02
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Booth AJ;Csencsits-Smith K;Wood SC;Lu G;Lipson KE;Bishop DK
通讯作者：
Bishop DK
影响因子：
6.2
作者：
Kim, Irene;Wu, Gordon;Jordan, Stanley
通讯作者：
Jordan, Stanley