Effects of combination therapy with dipeptidyl peptidase‐IV and histone deacetylase inhibitors in the non‐obese diabetic mouse model of type 1 diabetes. (18th April 2013)

• Record Type: Journal Article
• Authors: Cabrera, S. M.; Colvin, S. C.; Tersey, S. A.; Maier, B.; Nadler, J. L.; Mirmira, R. G.
• Is Part Of: Clinical and experimental immunology. Volume 172:Number 3(2013:Jun.)
• Page Start: 375
• Page End: 382
• Publication Date: 2013-04-18
• Subjects: Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12068
• Languages: English
• ISSNs: 0009-9104

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Type 1 diabetes (T1D) results from T helper type 1 (Th1)‐mediated autoimmune destruction of insulin‐producing β cells. Novel experimental therapies for T1D target immunomodulation, β 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 β cell inflammatory destruction while simultaneously shifting the immune response towards immune‐tolerizing regulatory T cells (T<sub>regs</sub>). 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 β 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 T<sub>reg</sub> percentage, and combination therapy with MK‐626 and vorinostat increased pancreatic lymph node T<sub>reg</sub> 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 β cell area, insulitis and T<sub>reg</sub> populations. Combinations of vorinostat and MK‐626 may serve as beneficial adjunctive therapy in clinical trials for T1D prevention or remission.</p> </abstract>