title: Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition.
abstract: OBJECTIVE
  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
  These data demonstrate that a combination of TLR2 tolerisation and DPP4 inhibition can reverse early-onset diabetes in NOD mice.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Kangnam-ku, Seoul, Korea.
authors.forename: D-H
authors.initials: DH
authors.lastname: Kim
authors.forename: J-C
authors.initials: JC
authors.lastname: Lee
authors.forename: M-K
authors.initials: MK
authors.lastname: Lee
authors.forename: K-W
authors.initials: KW
authors.lastname: Kim
authors.forename: M-S
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010879:Piperazines / Q000494:pharmacology*; D011236:Prediabetic State / Q000188:drug therapy* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000187:drug effects
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; D054873:Dipeptidyl-Peptidase IV Inhibitors; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010879:Piperazines; D051195:Toll-Like Receptor 2