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

Diabetologia. 2012 Dec;55(12):3308-17. doi: 10.1007/s00125-012-2723-x. Epub 2012 Sep 27.

Abstract

Aims/hypothesis: We have shown that chronic administration of the Toll-like receptor 2 (TLR2) agonist Pam3CSK(4) 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 Pam3CSK(4), 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 Pam3CSK(4)+DA-1229 but not by either Pam3CSK(4) or DA-1229 alone. Beta cell mass and the number of proliferating beta cells were significantly enhanced by Pam3CSK(4)+DA-1229, but not by either Pam3CSK(4) 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 Pam3CSK(4)+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 Pam3CSK(4)+DA-1229.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Dendritic Cells / metabolism
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Female
  • Flow Cytometry
  • Lipopeptides / pharmacology*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Piperazines / pharmacology*
  • Prediabetic State / drug therapy*
  • Prediabetic State / metabolism
  • Toll-Like Receptor 2 / drug effects

Substances

  • 4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one
  • Dipeptidyl-Peptidase IV Inhibitors
  • Lipopeptides
  • Pam(3)CSK(4) peptide
  • Piperazines
  • Toll-Like Receptor 2