Zou Jiaqi, Gao Xinpu, Liu Tengli, Liang Rui, Liu Yaojuan, Wang Guanqiao, Wang Le, Liu Na, Sun Peng, Wang Zhiping, Wang Shusen, Shen Zhongyang
Key Laboratory for Critical Care Medicine of the Ministry of Health, Tianjin First Center Hospital, Tianjin, China.
State Key Laboratory of Medicinal Chemical Biology, Tianjin, China.
Endocr J. 2018 Sep 27;65(9):943-952. doi: 10.1507/endocrj.EJ18-0158. Epub 2018 Jul 10.
Type 1 diabetes mellitus (T1DM) is a syndrome of loss of glucose homeostasis caused by the loss of β cell chronic autoimmunity against islet cells. Islet-specific epitopes coupled antigen presenting cells by Ethylenecarbodiimide (ECDI) is a promising strategy to induce antigen-specific tolerance. However, single epitope induced tolerance is insufficient to prevent the onset of T1DM. The aim of this study is to evaluate the efficacy of whole islet antigens in preventing the onset and progression of T1DM and identify the underlying immune mechanism in NOD mice. In this study, the whole islet antigens, derived from islet lysate isolated from BALB/c mice, were coupled to splenocytes of BALB/c mice by ECDI fixation (SP-Islet lysate), and then intravenously administrated to NOD mice. The results showed that, compared with control group, SP-Islet lysate group significantly decreased T1DM incidence and improved the survival of NOD mice. SP-Islet lysate treated mice had reduced insulitis score and autoantibody levels, and improved glucose tolerance and insulin/glucagon production. Furthermore, the effector memory T cells (T) were downregulated and regulatory T cells (Tregs) were upregulated by the SP-Islet lysate treatment, with reduced populations of Th1&Th17 cells. In conclusion, ECDI-fixed splenocytes carrying whole islet antigens effectively prevented the onset of T1DM in NOD mice, via suppressing the production of autoantibodies and inducing anergy of autoreactive T cells.
1型糖尿病（T1DM）是一种由于胰岛β细胞慢性自身免疫丧失导致葡萄糖稳态失衡的综合征。通过乙烯碳二亚胺（ECDI）将胰岛特异性表位与抗原呈递细胞偶联是诱导抗原特异性耐受的一种有前景的策略。然而，单一表位诱导的耐受不足以预防T1DM的发病。本研究的目的是评估全胰岛抗原在预防NOD小鼠T1DM发病和进展中的疗效，并确定其潜在的免疫机制。在本研究中，将从BALB/c小鼠分离的胰岛裂解物中获得的全胰岛抗原，通过ECDI固定与BALB/c小鼠的脾细胞偶联（SP-胰岛裂解物），然后静脉注射给NOD小鼠。结果显示，与对照组相比，SP-胰岛裂解物组显著降低了T1DM发病率，提高了NOD小鼠的存活率。经SP-胰岛裂解物处理的小鼠胰岛炎评分和自身抗体水平降低，葡萄糖耐量和胰岛素/胰高血糖素分泌改善。此外，SP-胰岛裂解物处理下调了效应记忆T细胞（Teff），上调了调节性T细胞（Tregs），Th1和Th17细胞数量减少。总之，携带全胰岛抗原的ECDI固定脾细胞通过抑制自身抗体产生和诱导自身反应性T细胞失能，有效预防了NOD小鼠T1DM的发病。
