Article

Diabetologia

, Volume 55, Issue 12, pp 3308-3317

Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition

  • D.-H. KimAffiliated withDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
  • , J.-C. LeeAffiliated withDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
  • , M.-K. LeeAffiliated withDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
  • , K.-W. KimAffiliated withDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
  • , M.-S. LeeAffiliated withDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineDepartment of Medicine and Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine Email author 

Abstract

Aims/hypothesis

We have shown that chronic administration of the Toll-like receptor 2 (TLR2) agonist Pam3CSK4 prevents diabetes in NOD mice by inducing TLR2 tolerance of dendritic cells (DCs). We have also reported that a novel dipeptidyl peptidase 4 (DPP4) inhibitor, DA-1229, could increase beta cell mass. Here we investigated whether a combination of DPP4 inhibition, with beneficial effects on beta cell mass, and TLR2 tolerisation, protecting beta cells from autoimmune destruction, could treat a model of established type 1 diabetes.

Methods

Diabetic NOD mice were treated with 100 μg Pam3CSK4, administered three times a week for 3 weeks, in combination with feeding with chow containing 0.3% DA-1229. Beta cell mass and proliferation were studied by immunohistochemistry. DC tolerance was assessed by studying diabetogenic CD4+ T cell priming after adoptive transfer and expression of costimulatory molecules on DCs by flow cytometry.

Results

We observed reversal of diabetes in NOD mice by Pam3CSK4+DA-1229 but not by either Pam3CSK4 or DA-1229 alone. Beta cell mass and the number of proliferating beta cells were significantly enhanced by Pam3CSK4+DA-1229, but not by either Pam3CSK4 or DA-1229 alone. Diabetogenic T cell priming by DCs and upregulation of costimulatory molecules after ex vivo stimulation were attenuated in mice treated with Pam3CSK4+DA-1229, indicating DC tolerance. The relative proportions of CD4+ T cells, CD8+ T cells, B cells, DCs, macrophages and regulatory T cells, and T-helper polarisation were unchanged by treatment with Pam3CSK4+DA-1229.

Conclusions/interpretation

These data demonstrate that a combination of TLR2 tolerisation and DPP4 inhibition can reverse early-onset diabetes in NOD mice.

Keywords

Dipeptidyl peptidase 4 Immune tolerance NOD TLR2 Treatment Type 1 diabetes