Type 1 diabetes (T1D) is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been hampered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells.

中文翻译：

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可溶性 RAGE 预防 1 型糖尿病扩大功能性调节性 T 细胞

1 型糖尿病 (T1D) 是一种无法治愈的自身免疫性疾病，有希望的治疗方法的临床转化受到可重复性危机的阻碍。在这里，在两个独立的研究中心，短期给予晚期糖基化终产物受体 (sRAGE) 的拮抗剂可以预防鼠糖尿病。sRAGE 治疗增加了胰岛、胰腺淋巴结和脾脏内的调节性 T 细胞 (Tregs)，增加了胰岛胰岛素的表达和功能。Treg 耗竭消除了糖尿病保护，并显示依赖于使用敲除小鼠拮抗 RAGE。用 RAGE 配体处理的人类 Treg 下调抑制、迁移和 Treg 稳态的基因（FOXP3、IL7R、TIGIT、JAK1、STAT3、STAT5b、CCR4）。抑制功能的丧失被 sRAGE 逆转，其中 Tregs 增加增殖并抑制常规 T 细胞分裂，证实 sRAGE 扩展了功能性人类 Tregs。这些结果突出了 sRAGE 作为预防糖尿病的有吸引力的治疗方法，在多个研究中心和人类 T 细胞中显示出疗效和可重复性。