Li J, Zhang K, Ye P, Wang S, Xia J
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430022, China.
Clin Exp Immunol. 2009 Sep;157(3):437-45. doi: 10.1111/j.1365-2249.2009.03982.x.
Both chemokine receptor 5 (CCR5) blockade and rapamycin (rapa) are effective in modulating transplant immunity and led to prolonged allograft survival, yet a great many grafts were ultimately lost to acute rejection. In this study we examined the inhibition of CCR5 in combination with the treatment with rapa in cardiac transplantation. Fully major histocompatibility complex-mismatched murine cardiac allograft models were randomized to five groups. They were administered with anti-CCR5 antibody or control antibody and rapa or phosphate-buffered saline (PBS), respectively. An additional group was treated with anti-CCR5 antibody, rapa and anti-CD25 antibody. Allograft rejection was investigated by flow cytometric analyses and enzyme-linked immunospot assay. Allografts treated with anti-CCR5 antibody plus rapa showed significantly prolonged survival (83 +/- 3 days, P < 0.001) compared with control antibody plus PBS-treated allografts (6 +/- 1 days). Treatment with anti-CCR5 monoclonal antibody (mAb) plus rapa inhibited significantly the progression of chronic rejction. Further analysis of donor hearts in the anti-CCR5 antibody plus rapa-treated group demonstrated increased infiltration of CD4(+)CD25(+)forkhead box P3(+) regulatory T cells, and depletion of CD25(+) cells resulted in acute rejection of allografts in 18 +/- 1 day. CCR5 blockade in combination with rapa is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated by CD25(+) T cell recruitment and control of T lymphocyte proliferation.
趋化因子受体5（CCR5）阻断和雷帕霉素（rapa）在调节移植免疫方面均有效，并能延长同种异体移植物存活时间，但仍有许多移植物最终因急性排斥反应而丧失。在本研究中，我们检测了在心脏移植中CCR5抑制与rapa联合治疗的效果。将完全主要组织相容性复合体不匹配的小鼠心脏同种异体移植模型随机分为五组。分别给予抗CCR5抗体或对照抗体以及rapa或磷酸盐缓冲盐水（PBS）。另外一组接受抗CCR5抗体、rapa和抗CD25抗体治疗。通过流式细胞术分析和酶联免疫斑点测定法研究同种异体移植排斥反应。与对照抗体加PBS处理的同种异体移植物（6±1天）相比，抗CCR5抗体加rapa处理的同种异体移植物存活时间显著延长（83±3天，P<0.001）。抗CCR5单克隆抗体（mAb）加rapa治疗显著抑制了慢性排斥反应的进展。对抗CCR5抗体加rapa治疗组的供体心脏进行进一步分析发现，CD4(+)CD25(+)叉头框P3(+)调节性T细胞浸润增加，而CD25(+)细胞的耗竭导致同种异体移植物在18±1天发生急性排斥反应。在一个强大的小鼠模型中，CCR5阻断与rapa联合可有效预防急性和慢性排斥反应。这种作用是由CD25(+)T细胞募集和T淋巴细胞增殖控制介导的。
