Emergency Centre, Zhongnan Hospital, Wuhan University, Wuhan, China.
Clin Exp Immunol. 2013 Sep;173(3):544-52. doi: 10.1111/cei.12128.
A previous paper has reported that blockade of NKG2D was effective in protecting allograft in murine models of cardiac transplantation, but the mechanism of NKG2D blockade on attenuated cardiac allograft vasculopathy (CAV) was still unknown. In our current study, we found that wild-type recipients treated with anti-NKG2D monoclonal antibody (mAb) plus cytotoxic T lymphocyte antigen (CTLA)-4-immunoglobulin (I)g showed prolonged allograft survivals (>90 days, P < 0·001) significantly and attenuated CAV. These in-vivo results correlated with reduced alloantibody production, low expression of interleukin (IL)-17 and IL-6, while infiltration of regulatory T cells increased. IL-6 administration induced shorter allograft survival and higher CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients, whereas IL-17 had no significant effect on allograft survival and CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients. Furthermore, the prolonged allograft survival induced by NKG2D blockade was abrogated partially with depletion of regulatory T cells. In conclusion, blockade of NKG2D combined with CTLA-4-Ig attenuated CAV and this effect was associated with lower alloantibody production, inhibited IL-6 expression and enhanced expansion of regulatory T cells.
先前的一篇论文报道称，阻断 NKG2D 在小鼠心脏移植模型中可有效保护同种异体移植物，但 NKG2D 阻断对减轻心脏同种异体血管病（CAV）的机制仍不清楚。在我们目前的研究中，我们发现野生型受者接受抗 NKG2D 单克隆抗体（mAb）加细胞毒性 T 淋巴细胞抗原（CTLA）-4-免疫球蛋白（Ig）治疗后，移植物存活率显著延长（>90 天，P<0.001），CAV 减轻。这些体内结果与减少同种抗体产生、白细胞介素（IL）-17 和 IL-6 表达降低以及调节性 T 细胞浸润增加相关。IL-6 给药可诱导 CTLA-4-Ig 加抗 NKG2D mAb 治疗受者的移植物存活时间缩短和 CAV 分级升高，而 IL-17 对 CTLA-4-Ig 加抗 NKG2D mAb 治疗受者的移植物存活时间和 CAV 分级没有显著影响。此外，NKG2D 阻断诱导的移植物存活延长部分被调节性 T 细胞耗竭所阻断。总之，阻断 NKG2D 联合 CTLA-4-Ig 可减轻 CAV，其作用与较低的同种抗体产生、抑制 IL-6 表达和增强调节性 T 细胞扩增有关。
