Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes
Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes
复制标题
表达 PD-L1 的工程血小板可逆转新发 1 型糖尿病
DOI：
10.1002/adma.201907692
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发表时间：
2020
影响因子：
29.4
通讯作者：
Gu Zhen
中科院分区：
文献类型：
--
作者：
Zhang Xudong;Kang Yang;Wang Jinqiang;Yan Junjie;Chen Qian;Cheng Hao;Huang Peng;Gu Zhen
1型糖尿病（T1 D）的发病机制是由胰岛特异性自身反应性T细胞破坏胰岛素产生β细胞引起的。抑制胰岛特异性自身反应性T细胞以拯救β细胞是治疗新发T1 D的有希望的方法。免疫检查点信号轴程序性死亡-1/程序性死亡-配体1（PD-1/PD-L1）可有效调节T细胞活性，预防自身免疫攻击。在这里，巨核细胞祖细胞被基因工程改造成过表达PD-L1以产生免疫抑制性血小板。PD-L1过表达血小板（称为PD-L1血小板）在炎症胰腺中积累，并可能抑制新发高血糖非肥胖糖尿病（NOD）小鼠中胰腺自身反应性T细胞的活性，保护胰岛素产生β细胞免受破坏。此外，PD-L1血小板治疗还增加了调节性T细胞（TCFs）的百分比，并维持了胰腺的免疫耐受性。研究表明，PD-L1血小板对β-细胞的拯救可以有效地维持新的高血糖NOD小鼠的正常血糖并逆转糖尿病。
The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin‐producing β‐cells by islet‐specific autoreactive T cells. Inhibition of islet‐specific autoreactive T cells to rescue β‐cells is a promising approach to treat new‐onset T1D. The immune checkpoint signal axis programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD‐L1 to produce immunosuppressive platelets. The PD‐L1‐overexpressing platelets (designated PD‐L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non‐obese diabetic (NOD) mice, protecting the insulin‐producing β‐cells from destruction. Moreover, PD‐L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of β‐cells by PD‐L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.