The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts.
The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts.
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DOI：
10.1016/j.lfs.2015.02.012
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发表时间：
2015-10
期刊：
影响因子：
6.1
通讯作者：
A. Kemter;S. Scheu;N. Hüser;C. Ruland;B. Schumak;Matthias Findeiß;Zhangjun Cheng;V. Assfalg;V. Arolt;A. Zimmer;J. Alferink
中科院分区：
文献类型：
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作者：
A. Kemter;S. Scheu;N. Hüser;C. Ruland;B. Schumak;Matthias Findeiß;Zhangjun Cheng;V. Assfalg;V. Arolt;A. Zimmer;J. Alferink
目的心脏移植的急性排斥反应是限制心脏移植受者生存的主要危险因素。排斥反应是由树突状细胞（DC）介导的宿主T细胞激活引发的，其中包括CD4+T辅助细胞（TH）1-和TH17细胞。大麻素受体2 （CB2）是细胞免疫应答的重要调节剂。然而，其在同种异体心脏移植排斥反应中的作用尚未得到研究。本研究利用体外生成的骨髓源性dc （bm - dc）和CB2敲除小鼠（Cnr2−/−）的CD4+T细胞，研究了CB2对成熟dc细胞因子释放的影响及其对CD4+T细胞分化的影响。我们在一个完全主要组织相容性复合物错配的小鼠心脏移植模型中使用cnr2 - / -小鼠进一步评估了CB2在急性同种异体移植排斥反应中的功能作用。关键发现：与野生型受体相比，nr2−/−小鼠的同种异体移植排斥反应加速。体外刺激BM-DCs显示促炎细胞因子白介素(IL)-6、IL-1β、肿瘤坏死因子（TNF）和免疫调节细胞因子TGF-β的分泌增强。此外，在nr2−/−bm - dc中，TH1/TH17促进细胞因子IL-12和IL-23的分泌增加。此外，Cnr2−/−CD4+T细胞分化为干扰素(IFN)-γ或il -17产生效应细胞的能力增强。结果表明，CB2可通过adc调节体外细胞因子反应，并直接影响TH1/TH17的分化。这些发现以及在nr2−/−小鼠中异体移植排斥反应增强的事实表明，CB2可能是器官移植中有希望的治疗靶点。
AimsAcute rejection of cardiac allografts is a major risk factor limiting survival of heart transplant recipients. Rejection is triggered by dendritic cell (DC) mediated activation of host T cells, amongst others CD4+T helper (TH)1- and TH17 cells. The cannabinoid receptor 2 (CB2) is an important modulator of cellular immune responses. However, its role in cardiac allograft rejection has not been studied so far.Main methodsHere, we examined the effect of CB2 on cytokine release by mature DCs and its impact on CD4+T cell differentiation by utilizingin vitrogenerated bone marrow-derived DCs (BM-DCs) and CD4+T cells from CB2 knockout (Cnr2−/−) mice. We further assessed the functional role of CB2 in acute allograft rejection usingCnr2−/−mice in a fully major histocompatibility complex-mismatched mouse cardiac transplantation model.Key findingsCardiac allograft rejection was accelerated inCnr2−/−mice compared to wild type recipients.In vitrostimulation of BM-DCs showed enhanced secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF) and the immunomodulatory cytokine TGF-β. Furthermore, secretion of the TH1/TH17 promoting cytokines IL-12 and IL-23 was increased inCnr2−/−BM-DCs. In addition,Cnr2−/−CD4+T cells showed an enhanced capacity to differentiate into interferon (IFN)-γ- or IL-17-producing effector cells.SignificanceThese results demonstrate that CB2 modulatesin vitrocytokine responsesviaDCs and directlyviaits influence on TH1/TH17 differentiation. These findings and the fact that allograft rejection is enhanced inCnr2−/−mice suggest that CB2 may be a promising therapeutic target in organ transplantation.