Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes

S. M. Cabrera, S. C. Colvin, S. A. Tersey, B. Maier, J. L. Nadler, R. G. Mirmira

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Summary: 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 (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 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 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 β 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.

Original languageEnglish (US)
Pages (from-to)375-382
Number of pages8
JournalClinical and Experimental Immunology
Volume172
Issue number3
DOIs
StatePublished - Jun 1 2013

Keywords

  • Animal models (mice/rats)
  • Autoimmunity
  • Insulitis
  • Lymph nodes
  • Non-obese diabetic (NOD) mouse
  • Regulatory T cells
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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