Zhang Shiyun, Dai Qianqian, Zhang Bin, Liu Siyang, Wang Ying, Zhang Yixue, Chen Dongyue, Zong Ningning, Wang Hongwei, Ding Jingjing, Gao Qian, Wen Yanting
Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China.
Department of Respiratory Medicine, Jiangsu Key Laboratory of Molecular Medicine, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Ann Transl Med. 2021 Nov;9(22):1642. doi: 10.21037/atm-21-3329.
Type 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet β cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintains Tregs' homeostasis.
We built a later-stage streptozotocin (STZ)-induced T1D mouse model. Syngeneic bone marrow transplantation (syn-BMT) was performed 20 days after the onset of diabetes in combination with BKM120 (a PI3K inhibitor). Meanwhile, another group of STZ-diabetic mice were transplanted with bone marrow cells cocultured with BKM120 for 24 h. Fasting glucose and glucose tolerance were recorded during the entire experimental observation after syn-BMT. Samples were collected 126 days after syn-BMT. Hematoxylin and eosin (H&E) staining was used to detect the effect of PI3K inhibitor combined with syn-BMT on morphology of the T1D pancreas. CD4CD25 T cells and CD4CD25 T cells were sorted by magnetic cell sorting (MACS), then fluorescence activated cell sorting (FACS) and quantitative real-time PCR (qPCR) were used to detect the effect of PI3K inhibitor on modulating immune disorder and restoring the function of Treg cells.
Our investigation showed syn-BMT in combination with BKM120 effectively maintained normoglycemia in later-stage T1D. The disease remission effects may be induced by the rebalance of Th17/Tregs dysregulation and restoration of Tregs' immunosuppressive function by BKM120 after syn-BMT.
These results may reveal important connections for PI3K/Akt inhibition and Tregs' homeostasis in T1D after transplantation. AHSCT combining immunoregulatory strategies such as PI3K inhibition may be a promising therapeutic approach in later-stage T1D.
1型糖尿病（T1D）是一种多因素自身免疫性疾病，其特征在于T细胞介导的胰岛β细胞免疫破坏。自体造血干细胞移植（AHSCT）已成为新发T1D患者的一种新策略，但对于那些诊断较晚的患者则不然。调节性T细胞（Tregs）的紊乱可能导致晚期T1D移植后反应不佳。抑制磷酸肌醇3-激酶（PI3K）/Akt信号传导可维持Tregs的稳态。
我们构建了晚期链脲佐菌素（STZ）诱导的T1D小鼠模型。在糖尿病发病20天后进行同基因骨髓移植（syn-BMT），并联合使用BKM120（一种PI3K抑制剂）。同时，另一组STZ诱导的糖尿病小鼠移植与BKM120共培养24小时的骨髓细胞。在syn-BMT后的整个实验观察期间记录空腹血糖和葡萄糖耐量。在syn-BMT后126天收集样本。苏木精和伊红（H&E）染色用于检测PI3K抑制剂联合syn-BMT对T1D胰腺形态的影响。通过磁珠细胞分选（MACS）对CD4CD25 T细胞和CD4CD25 T细胞进行分选，然后使用荧光激活细胞分选（FACS）和定量实时PCR（qPCR）检测PI3K抑制剂对调节免疫紊乱和恢复Treg细胞功能的影响。
我们的研究表明，syn-BMT联合BKM120可有效维持晚期T1D的正常血糖水平。疾病缓解效果可能是由于syn-BMT后Th17/Tregs失调的重新平衡以及BKM120恢复了Tregs的免疫抑制功能所致。
这些结果可能揭示了移植后T1D中PI3K/Akt抑制与Tregs稳态之间的重要联系。AHSCT联合PI3K抑制等免疫调节策略可能是晚期T1D的一种有前景的治疗方法。
