Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes
Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes
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DOI：
10.1038/s42255-019-0061-8
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发表时间：
2019-05-01
影响因子：
20.8
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
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作者：
Dirice, Ercument;Kahraman, Sevim;Kulkarni, Rohit N.
1型糖尿病(T1D)的特征是自身反应性免疫细胞的胰岛浸润和几乎完全丧失的β细胞(1)。恢复产生胰岛素的β细胞，结合免疫调节以抑制自身免疫攻击，已成为对抗T1D(2-4)的潜在方法。在这里，我们报告了在两种雌性非肥胖糖尿病(NOD)小鼠模型中，在生命早期增加β细胞质量，导致T细胞的免疫调节，减少胰岛浸润和降低β细胞凋亡，这些共同保护它们免受T1D的发展。动物表现出改变的β细胞抗原；胰岛移植研究表明，在节点肝脏特异性胰岛素受体基因敲除(LIRKO)模型中，移植物存活时间延长。过继转移NOD-LIRKO小鼠的脾细胞可预防糖尿病前期NOD小鼠糖尿病的发生。由于T-reg细胞耗尽导致NOD-LIRKO小鼠糖尿病，观察到脾中CD4(+)CD25(+)Foxp3(+)调节性T细胞(T-reg)种群的显著增加是受保护表型的基础。致病T细胞中T-reg细胞的增加和转化生长因子-β/SMAD家族成员3信号通路的激活有利于降低对β细胞的杀伤能力。这些数据支持一个以前未知的观察结果，即在免疫细胞侵袭胰岛之前单独启动β细胞增殖会改变β细胞的身份，降低效应者T细胞的病理性自我反应，并增加T-reg细胞以防止T1D的进展。
Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a nearly complete loss of beta cells(1). Restoration of insulin-producing beta cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D(2-4). Here we report that enhancing beta-cell mass early in life, in two models of female non-obese diabetic (NOD) mice, results in immunomodulation of T cells, reduced islet infiltration and lower beta-cell apoptosis, which together protect them from developing T1D. The animals displayed altered beta-cell antigens; islet transplantation studies showed prolonged graft survival in the NOD-liver-specific insulin receptor knockout (LIRKO) model. Adoptive transfer of splenocytes from NOD-LIRKO mice prevented development of diabetes in prediabetic NOD mice. A substantial increase in the splenic CD4(+)CD25(+)Foxp3(+) regulatory Tcell (T-reg) population was observed to underlie the protected phenotype since T-reg-cell depletion rendered NOD-LIRKO mice diabetic. An increase in T-reg cells coupled with activation of transforming growth factor-beta/SMAD family member 3 signalling pathway in pathogenic T cells favoured reduced ability to kill beta cells. These data support a previously unidentified observation that initiating beta-cell proliferation, alone, before islet infiltration by immune cells alters the identity of beta cells, decreases pathological self-reactivity of effector T cells and increases T-reg cells to prevent the progression of T1D.