雷帕霉素对1型糖尿病小鼠免疫功能的影响及其分子机制

摘要

Objective To study the effect of rapamycin on immune function of T1DM mouse and its molecular mechanism. Methods T1DM model of mice was estabolished by multiple low dose of streptozotocin peritoneal injections. Blood glucose, body weight, food intake and water drinking were observed. And islet pathology, ultrastructure, apoptosis and autophagy of kidney, spleen, thymus and pancreas as well as the swarming of spleen T cells were examined. Results Papamycin-treated T1DM mice showed that: (1) blood glucose, food intake and amount of water drinking were increased, and BW decreased; (2) Insulitis worsened and expressions of LC3, beclin-1 and caspase-3 were increased; (3) Autophagy and apoptosis of the four organs occurred; (4) Numbers of Th2 cells and CD4+ CD25+ T cell were increased and Thl cells decreased.Conclusions Rapamycin can induce an immune tolerance with immune suppresive effects, but can induce autophagy of islet cells with abnormal metabolism and worsened complications.%目的 研究雷帕霉素对1型糖尿病(T1DM)小鼠的影响及其分子机制.方法 40 mg/kg的STZ腹腔注射C57BL/6小鼠连续5 d建立T1DM模型,正常和T1DM小鼠按2 mg/kg腹腔注射RAPA连续两周.监测血糖、体重、进食量和饮水量;观测胰岛炎、主要脏器的超微结构和凋亡和自噬的发生;检测脾脏Th1/Th2分群和调节性T细胞.结果 RAPA对正常小鼠一般特性及主要脏器的超微结构无明显影响.但可使T1DM小鼠血糖升高、体重下降、采食和饮水量增加(P<0.05),并加重其胰岛炎程度;诱导其胰腺、肾脏、脾脏和胸腺细胞自噬或凋亡,并使LC3、Beclin1、Caspase-3的表达增加;减少正常和T1DM小鼠的Th1细胞,增加Th2细胞,并上调CD4+CD25+T细胞的数量.结论 RAPA既可诱导免疫耐受,发挥免疫抑制作用,又可通过白噬直接破坏胰岛从而加重T1DM代谢紊乱和并发症.