UNASSIGNED: Female NOD mice were treated with anti-CD226 between 7-8 weeks of age and then monitored for diabetes incidence and therapeutic mechanism of action.
UNASSIGNED: Compared to isotype-treated controls, anti-CD226 treated NOD mice showed reduced insulitis severity at 12 weeks and decreased disease incidence at 30 weeks. Flow cytometric analysis performed five weeks post-treatment demonstrated reduced proliferation of CD4+ and CD8+ effector memory T cells in spleens of anti-CD226 treated mice. Phenotyping of pancreatic Tregs revealed increased CD25 expression and STAT5 phosphorylation following anti-CD226, with splenic Tregs displaying augmented suppression of CD4+ T cell responders in vitro. Anti-CD226 treated mice exhibited reduced frequencies of islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP)-reactive CD8+ T cells in the pancreas, using both ex vivo tetramer staining and single-cell T cell receptor sequencing (scTCR-seq) approaches. 51Cr-release assays demonstrated reduced cell-mediated lysis of beta-cells by anti-CD226-treated autoreactive cytotoxic T lymphocytes.
UNASSIGNED: CD226 blockade reduces T cell cytotoxicity and improves Treg function, representing a targeted and rational approach for restoring immune regulation in type 1 diabetes.
■在7-8周龄之间用抗CD226治疗雌性NOD小鼠,然后监测糖尿病发病率和治疗作用机制。
■与同种型处理的对照相比,抗CD226治疗的NOD小鼠在12周时胰岛炎严重程度降低,在30周时发病率降低.在治疗后五周进行的流式细胞术分析显示,在抗CD226治疗的小鼠的脾脏中CD4+和CD8+效应记忆T细胞的增殖减少。胰腺Tregs的表型显示抗CD226后CD25表达和STAT5磷酸化增加,脾Tregs在体外显示对CD4T细胞反应者的抑制增强。抗CD226治疗的小鼠表现出胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白(IGRP)反应性CD8T细胞在胰腺中的频率降低,使用离体四聚体染色和单细胞T细胞受体测序(scTCR-seq)方法。51个Cr释放试验证明了抗CD226处理的自身反应性细胞毒性T淋巴细胞对β细胞的细胞介导的裂解减少。
■CD226阻断可降低T细胞毒性并改善Treg功能,代表了恢复1型糖尿病免疫调节的针对性和理性方法。
■关于该主题的已知情况?:共刺激受体CD226在激活后被上调,并在NK细胞亚群上高度表达,骨髓细胞,和效应T细胞。CD226中的单核苷酸多态性(rs763361;C>T)导致与1型糖尿病遗传易感性相关的Gly307Ser错义突变。在FoxP3+Tregs中Cd226的整体敲除和条件性Cd226敲除降低NOD小鼠的胰岛炎严重程度和糖尿病发病率,表明CD226在疾病发病机制中的关键作用。关键问题是什么?:CD226阻断能否降低T细胞毒性并改善Treg功能以减少NOD小鼠的糖尿病发病率?有什么新发现?抗CD226治疗可减少胰岛炎,发病率下降,并抑制脾CD4+和CD8+效应记忆T细胞增殖。来自抗CD226处理的小鼠的胰腺Treg表现出增加的CD25表达;脾Treg表现出增强的STAT5磷酸化和体外抑制能力。抗CD226治疗降低IGRP特异性胰腺CD8+T细胞频率,和减少自身反应性CD8+T细胞介导的β细胞体外裂解。在可预见的未来,这种对临床实践的影响如何?:CD226阻断可以减少自身反应性T细胞的细胞毒性,增强Treg功能,在高危或近期发病的1型糖尿病病例中,疾病进展缓慢。