超激动性CD28通过调节性T细胞的扩增来预防肾脏缺血性损伤。

Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell.

作者信息

Liang Yiran, Li Yan, Kuang Qing, Ding Xiaoqiang, Wei Zheng, Fang Yi

机构信息

Department of Nephrology, Zhongshan Hospital, Shanghai, China.

出版信息

Am J Nephrol. 2017;45(5):389-399. doi: 10.1159/000470918. Epub 2017 Mar 29.

DOI:10.1159/000470918

PMID:28355607

Abstract

BACKGROUND

Regulatory T (Treg) cells are a highly suppressive subset of CD4+ lymphocytes and have recently been proved to be crucial to suppress the inflammatory responses of ischemic kidney injury. CD28 superagonists (CD28sa) are monoclonal antibodies that preferentially expand Treg cells without a T-cell receptor and a costimulatory signal. This study aims to test the protection and discover the mechanisms of CD28sa treatment against renal ischemia-reperfusion (IR) injury (IRI).

METHODS

Male C57BL/6N mice were treated with CD28sa via peritoneal injection (0.1 mg) 6 days before the induction of IRI, or with 18-min ischemic precondition (IPC). IRI was induced by bilateral clamping of renal pedicles for 35 min followed by reperfusion. The role of Treg expansion in renal protection conferred by CD28sa treatment was examined using anti-CD25 antibody.

RESULTS

CD28sa treatment alone significantly increased the percentage of Treg cells in the spleen (18.10 ± 2.00 vs. 6.64 ± 0.86%, p < 0.01), peripheral blood (16.43 ± 5.94 vs. 2.57 ± 1.09%, p < 0.01), and kidney (2.69 ± 0.90 vs. 0.53 ± 0.14%, p < 0.01) of C57BL/6N mice 6 days after the administration. Mice pretreated with CD28sa or IPC had less renal injury at 24 h after IRI with attenuation of renal tubular damage and lower serum creatinine compared with the mice that underwent renal IRI alone. The number of infiltrating macrophages in the kidney and IFN-γ secreting CD4+ T cells in peripheral blood were diminished in the CD28sa-IR group and the IPC-IR group. The renal protection bestowed by CD28sa or IPC was abolished by anti-CD25 antibody administration.

CONCLUSIONS

Treg expansion induced by CD28sa ameliorated renal IRI.

摘要

背景

调节性T（Treg）细胞是CD4+淋巴细胞中具有高度抑制作用的亚群，最近已被证明对抑制缺血性肾损伤的炎症反应至关重要。CD28超激动剂（CD28sa）是一种单克隆抗体，可在无T细胞受体和共刺激信号的情况下优先扩增Treg细胞。本研究旨在测试CD28sa治疗对肾缺血再灌注（IR）损伤（IRI）的保护作用并发现其机制。

方法

雄性C57BL/6N小鼠在IRI诱导前6天通过腹腔注射（0.1mg）给予CD28sa，或进行18分钟的缺血预处理（IPC）。通过双侧夹闭肾蒂35分钟然后再灌注诱导IRI。使用抗CD25抗体检查Treg扩增在CD28sa治疗赋予的肾保护中的作用。

结果

单独使用CD28sa治疗可显著增加给药6天后C57BL/6N小鼠脾脏（18.10±2.00对6.64±0.86%，p<0.01）、外周血（16.43±5.94对2.57±1.09%，p<0.01）和肾脏（2.69±0.90对0.53±0.14%，p<0.01）中Treg细胞的百分比。与单独接受肾IRI的小鼠相比，用CD28sa或IPC预处理的小鼠在IRI后24小时肾损伤较轻，肾小管损伤减轻，血清肌酐较低。CD28sa-IR组和IPC-IR组肾脏中浸润的巨噬细胞数量和外周血中分泌IFN-γ的CD4+T细胞数量减少。给予抗CD25抗体可消除CD28sa或IPC赋予的肾保护作用。