Diabetes Center, Indiana Biosciences Research Institute, Indianapolis, IN, United States.
Department of Medicine, Endocrinology, Diabetes & Metabolism, Baylor College of Medicine, Houston, TX, United States.
Front Immunol. 2023 Aug 1;14:1207108. doi: 10.3389/fimmu.2023.1207108. eCollection 2023.
In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IA) in register 3 (R3), creating a bimolecular IA/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D.
To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28 mice.
InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.
在自发性 1 型糖尿病（T1D）非肥胖型糖尿病（NOD）小鼠中，胰岛素 B 链肽 9-23（B:9-23）可与 MHC Ⅱ类分子（IA）在 3 号寄存器（R3）结合，形成双分子 IA/胰岛素 B:9-23 3 号寄存器构象表位（InsB:R3）。先前，我们表明，使用胰岛素 B:R3 单克隆抗体构建的胰岛素 B:R3 特异性嵌合抗原受体（CAR）可以指导表达 CAR 的 CD8 T 细胞迁移到胰岛和胰腺淋巴结。针对胰岛抗原的调节性 T 细胞（Treg）可以广泛抑制胰岛内的各种致病性免疫细胞，并有效阻止胰岛破坏的进展。因此，我们假设 InsB:R3 特异性 Treg 将抑制胰岛内的自身免疫反应，并有效地预防 T1D。
为了验证我们的假设，我们生成了 InsB:R3-Treg，并在自发性 T1D NOD.CD28 小鼠中测试了它们的疾病保护作用。
InsB:R3-CAR 表达的 Treg 在与 InsB:R3 抗原结合时会分泌以 IL-10 为主的细胞因子。单次输注 InsB:R3 Treg 可使 95%的治疗小鼠延迟 T1D 发病，其中 35%的小鼠在两个健康寿命内维持血糖正常，容易归巢到相关靶点，而对照 Treg 则不能。我们的数据表明，针对 MHC Ⅱ类：胰岛素肽表位（MHCII/Insulin）的 Treg 比缺乏胰岛抗原特异性的多克隆 Treg 更有效地保护小鼠免受 T1D 的侵害，这表明 MHC II/胰岛素特异性 Treg 方法是一种安全预防 T1D 的有前途的免疫治疗方法。
