Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes.
Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes.
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作者：
Jurewicz M;Yang S;Augello A;Godwin JG;Moore RF;Azzi J;Fiorina P;Atkinson M;Sayegh MH;Abdi R
许多临床试验正在进行中，以测试间充质干细胞（MSC）是否能有效治疗包括1型糖尿病在内的各种疾病。虽然这种细胞疗法有很大的希望，MSC的最佳来源尚未确定与主要组织相容性复合体匹配。在这里，我们通过测试从NOR小鼠品系获得的同源MSC逆转NOD小鼠中最近发作的1型糖尿病的能力来研究这个问题，以及确定NOR MSC在体内的免疫调节作用。NOR间充质干细胞在自身反应性T细胞增殖和树突状细胞（DC）生成的背景下，其在体外的免疫调节功能进行了评价。还检查了NOR MSC疗法对NOD小鼠中新近发作的高血糖症的逆转和对免疫原性细胞亚群的体内作用。NOR MSC显示通过PD-L1抑制致糖尿病性T细胞增殖，并主要通过IL-6依赖性机制抑制髓样/炎性DC的产生。NOR MSC治疗实验性1型糖尿病导致高血糖症的长期逆转，并且治疗显示改变致糖尿病细胞因子谱，减少胰腺淋巴结中的T细胞效应子频率，改变抗原呈递细胞频率，并增加DC的浆细胞样亚群的频率。这些研究证明了同源MSC治疗在逆转实验性1型糖尿病中的独特益处。这些数据将有利于未来使用MSC治疗1型糖尿病的临床试验。
A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo. NOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined. NOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs. These studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes.