As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3+ Treg-cell expansion in the spleen of wild-type mice but not in Gitr−/− mice. G3C/cps also induced the expansion of nonconventional Cd4+Cd25−/lowFoxp3lowGitrint/high (GITR single-positive [sp]) Tregs. Both Cd4+Cd25+GitrhighFoxp3+ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.

中文翻译：

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微囊化 G3C 杂交瘤细胞移植物通过扩增 Gitr+ Treg 细胞延迟 NOD 小鼠自发性糖尿病的发作

作为终生补充胰岛素的替代方案，增强 1 型糖尿病患者的免疫耐受可以防止胰岛 β 细胞的自身免疫性破坏。本研究旨在评估触发糖皮质激素诱导的 TNFR 相关 (Gitr) 共刺激受体的 G3c 单克隆抗体 (mAb) 是否促进 SV129（野生型）和糖尿病-易感的 NOD 小鼠。G3c mAb 通过包裹在基于海藻酸盐的微胶囊 (G3C/cps) 中的 G3C 杂交瘤细胞递送 3 周，在野生型小鼠的脾脏中诱导 Foxp3+ Treg 细胞扩增，但在 Gitr-/- 小鼠中则不然。G3C/cps 还诱导了非常规 Cd4+Cd25-/lowFoxp3lowGitrint/high（GITR 单阳性 [sp]）Treg 的扩增。Cd4+Cd25+GitrhighFoxp3+ 和 GITRsp Tregs（也包括抗原特异性细胞）在 G3C/cps 处理的 NOD 小鼠的脾脏和胰腺中扩增，并且 G3C/cps 处理的完整胰岛数量高于空的cps 处理和未处理的动物。因此，除了两只 G3C/cps 治疗的小鼠之外，所有小鼠都没有患上糖尿病，并且除了一只以外的所有小鼠都存活到了 24 周的研究结束。总之，长期的 Gitr 触发诱导 Treg 扩张，从而延迟/预防 NOD 小鼠的糖尿病发展。这种治疗方法可能具有治疗炎症和自身免疫性疾病的有希望的临床潜力。除了两只 G3C/cps 治疗的小鼠之外，所有小鼠都没有患上糖尿病，并且除了一只以外的所有小鼠都存活到了 24 周的研究结束。总之，长期的 Gitr 触发诱导 Treg 扩张，从而延迟/预防 NOD 小鼠的糖尿病发展。这种治疗方法可能具有治疗炎症和自身免疫性疾病的有希望的临床潜力。除了两只 G3C/cps 治疗的小鼠之外，所有小鼠都没有患上糖尿病，并且除了一只以外的所有小鼠都存活到了 24 周的研究结束。总之，长期的 Gitr 触发诱导 Treg 扩张，从而延迟/预防 NOD 小鼠的糖尿病发展。这种治疗方法可能具有治疗炎症和自身免疫性疾病的有希望的临床潜力。