ABSTRACT
Type 1 diabetes (T1D) results from T helper type 1 (Th1)-mediated autoimmune destruction of insulin-producing ß cells. Novel experimental therapies for T1D target immunomodulation, ß 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 ß cell inflammatory destruction while simultaneously shifting the immune response towards immune-tolerizing regulatory T cells (T(regs)). 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 ß 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(reg) percentage, and combination therapy with MK-626 and vorinostat increased pancreatic lymph node T(reg) 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 ß cell area, insulitis and T(reg) populations. Combinations of vorinostat and MK-626 may serve as beneficial adjunctive therapy in clinical trials for T1D prevention or remission.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Triazoles/administration & dosage , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Drug Evaluation, Preclinical , Drug Synergism , Drug Therapy, Combination , Female , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/pathology , Mice , Mice, Inbred NOD , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Transforming Growth Factor beta1/metabolism , VorinostatABSTRACT
Type 1 diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease resulting in islet ß cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. T1DM has classically been attributed to the pathogenic actions of auto-reactive effector T cells(Teffs) on the ß cell. Recent literature now suggests that a failure of a second T cell subtype, known as regulatory T cells (Tregs), plays a critical role in the development of T1DM. During immune homeostasis, Tregs counterbalance the actions of autoreactive Teff cells, thereby participating in peripheral tolerance. An imbalance in the activity between Teff and Tregs may be crucial in the breakdown of peripheral tolerance, leading to the development of T1DM. In this review, we summarize our current understanding of Treg function in health and in T1DM, and examine the effect of experimental therapies for T1DM on Treg cell number and function in both mice and humans.
