Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes
Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes
复制标题
DOI：
10.1111/cei.12068
复制
发表时间：
2013-06-01
影响因子：
4.6
通讯作者：
Mirmira, R. G.
中科院分区：
文献类型：
--
作者：
Cabrera, S. M.;Colvin, S. C.;Mirmira, R. G.
1 型糖尿病 (T1D) 是由 1 型辅助性 T (Th1) 介导的胰岛素生成细胞自身免疫性破坏所致。针对 T1D 的新型实验疗法以免疫调节、细胞存活和炎症为目标。我们在 T1D 的非肥胖糖尿病 (NOD) 小鼠模型中检查了二肽基肽酶 IV 抑制剂 MK-626 和组蛋白脱乙酰酶抑制剂伏立诺他的联合治疗。我们假设联合疗法可以通过提供免受细胞炎症破坏的保护来改善 T1D，同时将免疫反应转向免疫耐受的调节性 T 细胞 (Treg)。尽管 MK-626 和伏立诺他的单一疗法或联合疗法均未引起糖尿病 NOD 小鼠的疾病缓解，但与糖尿病对照小鼠相比，MK-626 和伏立诺他的组合增加了细胞面积并降低了平均胰岛素评分。在糖尿病前期 NOD 小鼠中，MK-626 单一疗法可改善糖耐量，降低平均胰岛炎评分并增加胰腺淋巴结 Treg 百分比，而 MK-626 和伏立诺他联合治疗可增加胰腺淋巴结 Treg 百分比。我们的结论是，使用 MK-626 和伏立诺他的单一疗法或联合疗法均不能诱导 NOD 小鼠的糖尿病缓解，但联合疗法似乎对细胞面积、胰岛素炎和 Treg 群体具有有益作用。伏立诺他和 MK-626 的组合可能在预防或缓解 T1D 的临床试验中作为有益的辅助治疗。
Type 1 diabetes (T1D) results from T helper type 1 (Th1)-mediated autoimmune destruction of insulin-producing cells. Novel experimental therapies for T1D target immunomodulation, cell survival and inflammation. We examined combination therapy with the dipeptidyl peptidase-IV inhibitor MK-626 and the histone deacetylase inhibitor vorinostat in the non-obese diabetic (NOD) mouse model of T1D. We hypothesized that combination therapy would ameliorate T1D by providing protection from cell inflammatory destruction while simultaneously shifting the immune response towards immune-tolerizing regulatory T cells (Tregs). Although neither mono- nor combination therapies with MK-626 and vorinostat caused disease remission in diabetic NOD mice, the combination of MK-626 and vorinostat increased cell area and reduced the mean insulitis score compared to diabetic control mice. In prediabetic NOD mice, MK-626 monotherapy resulted in improved glucose tolerance, a reduction in mean insulitis score and an increase in pancreatic lymph node Treg percentage, and combination therapy with MK-626 and vorinostat increased pancreatic lymph node Treg percentage. We conclude that neither single nor combination therapies using MK-626 and vorinostat induce diabetes remission in NOD mice, but combination therapy appears to have beneficial effects on cell area, insulitis and Treg populations. Combinations of vorinostat and MK-626 may serve as beneficial adjunctive therapy in clinical trials for T1D prevention or remission.