趋化因子受体 5 阻断剂与环孢素联合治疗可延长心脏移植小鼠模型的移植物存活期。

Combined treatment with chemokine receptor 5 blocker and cyclosporine induces prolonged graft survival in a mouse model of cardiac transplantation.

机构信息

Department of Cardiovascular Surgery, Union Hospital, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan, China.

出版信息

J Heart Lung Transplant. 2010 Apr;29(4):461-70. doi: 10.1016/j.healun.2009.09.019. Epub 2010 Jan 8.

DOI:10.1016/j.healun.2009.09.019

PMID:20060322

Abstract

BACKGROUND

Inhibition of chemokine receptor 5 (CCR5), a chemokine receptor expressed on activated T cells, is efficacious in modulating inflammation and immunity as well as in patients with human immunodeficiency virus infection. This study examined the effect and mechanism of CCR5 blockade in combination with cyclosporine in prolonging cardiac allograft survival in mice.

METHODS

Hearts from BALB/c mice were transplanted into C57BL/10 recipients. They were administrated with anti-CCR5 antibody (Ab) or control Ab and cyclosporine or phosphate-buffered (PBS) saline, respectively. To investigate the role of regulatory cells, naïve mice (secondary recipients) underwent adoptive transfer of splenocytes from anti-CCR5 Ab plus cyclosporine-treated recipients and cardiac allograft transplantation.

RESULTS

Compared with recipients treated with control Ab plus PBS, allografts treated with anti-CCR5 Ab and cyclosporine showed significantly prolonged survival (p < 0.001), markedly decreased CD4+ and CD8+ T cells (p < 0.005), and increased frequency of CD4+CD25+Foxp3+ regulatory cells (23.98% +/- 1.55% vs 6.30% +/- 0.57%, p < 0.005). Adoptive transfer of CD4+CD25+ splenocytes from anti-CCR5 Ab plus cyclosporine-treated recipients induced significantly prolonged survival in secondary recipients (p < 0.01 vs adoptive transfer from naïve mice and recipients depleted of CD25+ cells).

CONCLUSIONS

CCR5 blockade combined with cyclosporine is effective in protecting the cardiac allograft in a robust murine model. This effect is partly mediated by regulatory cell recruitment and control of effector cell infiltration.

摘要

背景

抑制趋化因子受体 5（CCR5），一种在激活的 T 细胞上表达的趋化因子受体，在调节炎症和免疫以及在人类免疫缺陷病毒感染患者中是有效的。本研究探讨了 CCR5 阻断联合环孢素在延长小鼠心脏移植存活中的作用和机制。

方法

将 BALB/c 小鼠的心脏移植到 C57BL/10 受体中。分别给予抗 CCR5 抗体（Ab）或对照 Ab 加环孢素或磷酸盐缓冲液（PBS）盐水。为了研究调节细胞的作用，幼稚小鼠（次级受体）接受来自抗 CCR5 Ab 加环孢素处理的受体的脾细胞过继转移，并进行心脏移植。

结果

与接受对照 Ab 加 PBS 处理的受体相比，用抗 CCR5 Ab 和环孢素处理的同种异体移植物的存活时间明显延长（p < 0.001），CD4+和 CD8+T 细胞明显减少（p < 0.005），CD4+CD25+Foxp3+调节细胞的频率增加（23.98% +/- 1.55% vs 6.30% +/- 0.57%，p < 0.005）。来自抗 CCR5 Ab 加环孢素处理的受体的 CD4+CD25+脾细胞的过继转移在次级受体中诱导了明显的存活时间延长（p < 0.01 与幼稚小鼠和耗尽 CD25+细胞的受体的过继转移相比）。