Li Minhuan, Lu Chenglin, Zhu Hao, Kang Xing, Wang Feng, Shao Lihua, Lu Xiaofeng, Chen Wei, Xia Xuefeng
Center of Pathology and Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University Nanjing 211100, Jiangsu Province, China.
Department of General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing 210008, Jiangsu Province, China.
Am J Transl Res. 2019 Jun 15;11(6):3438-3449. eCollection 2019.
Acute graft-versus-host disease (aGVHD) is one of the major complications after liver transplantation (LTx), which is induced by over-activation of T helper lymphocytes. Cenicriviroc (CVC) exerts its anti-inflammatory effect through inhibition of C-C chemokine receptor 5 (CCR5). However, whether CVC ameliorates aGVHD after liver transplantation remains unknown. In the present study, a rat aGVHD liver transplantation model (LTx-aGVHD) was constructed. CVC was intravenously injected from day 7 to day 14 after LTx. Liver and intestine samples were harvested to evaluate GVHD severity. Peripheral blood mononuclear cells (PBMCs) were collected and CCR5 antibodies were prepared to further explore the molecular mechanism . CVC significantly decreased the severity of GVHD associated skin and intestine injury. Quality of life of the LTx-GVHD rats was improved after CVC treatment. Flow cytometry further confirmed diminished peripheral donor-derived Th cells after CVC treatment. Molecularly, CVC treatment showed similar anti-inflammatory effects to CCR5 antibody injection. The level of CCR5, C-C motif chemokine ligand 5 (CCL5), and pro-inflammatory cytokines in the liver and intestines were inhibited after CVC treatment. Thus, CVC deactivated Th lymphocytes and decreased the severity of LTx-aGVHD through inhibition of CCR5.
急性移植物抗宿主病（aGVHD）是肝移植（LTx）后的主要并发症之一，由辅助性T淋巴细胞过度激活所致。西尼莫德（CVC）通过抑制C-C趋化因子受体5（CCR5）发挥抗炎作用。然而，CVC是否能改善肝移植后的aGVHD尚不清楚。在本研究中，构建了大鼠aGVHD肝移植模型（LTx-aGVHD）。LTx后第7天至第14天静脉注射CVC。采集肝脏和肠道样本以评估GVHD严重程度。收集外周血单个核细胞（PBMCs）并制备CCR5抗体以进一步探索分子机制。CVC显著降低了与GVHD相关的皮肤和肠道损伤的严重程度。CVC治疗后，LTx-GVHD大鼠的生活质量得到改善。流式细胞术进一步证实CVC治疗后外周供体来源的Th细胞减少。在分子水平上，CVC治疗显示出与注射CCR5抗体相似的抗炎作用。CVC治疗后，肝脏和肠道中CCR5、C-C基序趋化因子配体5（CCL5）和促炎细胞因子的水平受到抑制。因此，CVC通过抑制CCR5使Th淋巴细胞失活并降低LTx-aGVHD的严重程度。
