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  • Title: Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition.
    Author: Kim DH, Lee JC, Lee MK, Kim KW, Lee MS.
    Journal: Diabetologia; 2012 Dec; 55(12):3308-17. PubMed ID: 23011352.
    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.
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