Active suppression of diabetes after oral administration of insulin is determined by antigen dosage
Active suppression of diabetes after oral administration of insulin is determined by antigen dosage
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DOI：
10.1111/j.1749-6632.1996.tb21144.x
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发表时间：
1996-01-01
期刊：
影响因子：
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通讯作者：
Thivolet, C
中科院分区：
文献类型：
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作者：
Bergerot, I;Fabien, N;Thivolet, C
我们之前已经证明，每 2-3 天喂食 6 周大的雌性小鼠 20 单位人胰岛素，持续 15 或 30 天，可通过调节性 T 细胞的生成诱导积极的抑制机制，从而减少受辐射的 NOD 受体中糖尿病成功转移的数量。在本研究中，我们分析了抗原剂量和细胞注射获得保护的关键期的影响。因此，在糖尿病小鼠的 5 x 10 (6) T 细胞和来自小鼠脾脏的 5 x 10 (6) T 细胞的共转移实验中，比较了胰岛素喂养剂量的影响，每 2-3 天接受 10 单位、20 单位或 40 单位的胰岛素或盐水，持续 15 天。只有饲喂 20 个单位的小鼠的 T 淋巴细胞在过继转移过程中提供主动细胞保护，并显着延迟糖尿病发病 (p = 0.002)。在胰腺组织学分析中没有发现显着差异，表明没有预防胰岛炎。然而，接受来自 20 单位胰岛素喂养动物的 T 淋巴细胞的小鼠，其炎症形式较轻，严重浸润的胰岛比例明显较低。静脉注射致糖尿病 T 细胞后 7 天和 14 天注射调节性 T 细胞并没有改变接受者的糖尿病发病率曲线，这表明细胞相互作用和细胞运输延迟是决定因素。这些结果可能对人类具有重要的临床意义。总之，这项研究表明了抗原治疗在 I 型糖尿病中的重要性和局限性。抗原剂量是主动抑制的关键因素。在对糖尿病前期个体进行大规模预防试验之前，这种分析对于人类来说非常重要。
We have previously demonstrated that feeding six-week-old female mice with 20 units of human insulin every 2-3 days for 15 or 30 days induced an active mechanism of suppression through the generation of regulatory T cells that reduced the number of successful diabetic transfers in irradiated NOD recipients. In the present study, we analyzed the effects of antigen dosage and the critical period of cell injection to obtain protection. The effects of the dose of insulin feeding were therefore compared during cotransfer experiments of 5 x 10 (6) T cells from diabetic mice and 5 x 10 (6) T cells from the spleen of mice receiving 10 units, 20 units, or 40 units of insulin or saline every 2-3 days for 15 days. Only T lymphocytes from mice fed with 20 units conferred active cellular protection during adoptive transfer with a significant delay in diabetes onset (p= 0.002). No significant difference was noticed during histological analysis of pancreatic glands, indicating tha insulitis was not prevented. However, mice receiving T lymphocytes from the 20 units of insulin-fed animals had a milder form of inflammation, with a significantly lower percentage of severely infiltrated islets. Injecting regulatory T cells 7 days and 14 days after iv injection of diabetogenic T cells did not modify the incidence curves of diabetes in the recipients, suggesting that cellular interactions and delay in cell trafficking were determinants. These results may have important clinical implications in humans. In conclusion, this study indicates the importance but also the limits of antigen therapy in type I diabetes. Antigen dosage is a critical element for active suppression. Such analysis is important to perform in humans before the initiation of a large-scale prevention trial in prediabetic individuals.