The Tyrphostin Agent AG490 Prevents and Reverses Type 1 Diabetes in NOD Mice

BackgroundRecent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown. Materials and MethodsFemale NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed. ResultsAG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p ConclusionThe use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.背景：针对1型糖尿病（type 1 diabetes, T1D）的非肥胖糖尿病（non-obese diabetic, NOD）小鼠模型的近期研究佐证了酪氨酸激酶抑制剂（tyrosine kinase inhibitors）具备调控疾病发生发展的潜力。然而，AG490对1型糖尿病发生发展的治疗作用尚不明确。 材料与方法：将雌性NOD小鼠于4周龄或8周龄时开始以AG490（腹腔注射，i.p.，1 mg/只）或二甲基亚砜（DMSO）进行处理：先连续给药5周，随后每周给药1次，持续5周。后续开展糖尿病发生与/或逆转、胰岛炎、过继转移实验及其他机制相关研究。 结果：AG490可显著抑制1型糖尿病的发生（在两个不同时间点的检测结果分别为p = 0.02、p = 0.005）。与DMSO组完全无效（0%；0/10，Log-rank检验p = 0.003）相比，对新确诊糖尿病的NOD小鼠单药使用AG490可显著使受试动物（n = 23）达到疾病缓解，且停药后可维持正常血糖水平长达数月。值得注意的是，将经AG490处理的NOD小鼠的脾细胞过继转移给受体NOD-Scid小鼠后，并未诱发受体小鼠罹患糖尿病。经AG490处理的小鼠的CD4 T细胞及骨髓来源树突状细胞（bone marrow derived dendritic cells, BMDCs）中Foxp3的表达水平显著升高（p[原文此处统计值未完整给出]）。 结论：鉴于此类药物具备良好的安全性谱，其向糖尿病患者或糖尿病发病风险升高人群的临床转化具备坚实的理论基础。