Type 1 diabetes (T1D) is an autoimmune disease where pathogenic lymphocytes target autoantigens expressed in the pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 can home in on the pancreatic islets and prevent autoantibodies from recognizing β-cells. This study demonstrates that mAb43 binds to exocytotic sites on the β-cell surface, masking the antigenic exposure of ZnT8 and insulin following glucosestimulated insulin secretion. In vivo administration of mAb43 to nonobese diabetic (NOD) mice selectively increased the proportion of regulatory T-cells (Tregs) in the islet, resulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation and exhibited no adverse effects during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of β-cells suppresses the immunological cascade from B-cell antigen presentation to T-cell mediated β-cell destruction, providing a novel islet-targeted and antigen-specific immunotherapy to prevent and reverse clinical T1D.

中文翻译：

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细胞表面 ZnT8 抗体可预防和逆转小鼠自身免疫性糖尿病

1 型糖尿病 (T1D) 是一种自身免疫性疾病，其中致病性淋巴细胞针对胰岛中表达的自身抗原，导致产生胰岛素的 β 细胞遭到破坏。锌转运蛋白 8 (ZnT8) 是一种主要的自身抗原，大量存在于 β 细胞表面。这种独特的分子靶标具有保护 β 细胞免受 T1D 自身免疫攻击的潜力。我们之前的工作表明，针对细胞表面 ZnT8 的单克隆抗体 (mAb43) 可以定位胰岛并阻止自身抗体识别 β 细胞。这项研究表明，mAb43 与 β 细胞表面的胞吐位点结合，在葡萄糖刺激的胰岛素分泌后掩盖 ZnT8 和胰岛素的抗原暴露。对非肥胖糖尿病 (NOD) 小鼠体内施用 mAb43 可选择性增加胰岛中调节性 T 细胞 (Treg) 的比例，从而针对 T1D 发作以及逆转新发糖尿病提供完全且持续的保护。mAb43 诱导的自我耐受在治疗停止后是可逆的，并且在长期监测期间没有表现出不良影响。我们的研究结果表明，mAb43 屏蔽 β 细胞的抗原暴露，抑制了从 B 细胞抗原呈递到 T 细胞介导的 β 细胞破坏的免疫级联反应，提供了一种新型的胰岛靶向和抗原特异性免疫疗法，以预防和逆转临床症状。 T1D。