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

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

Induction of Tolerogenic Dendritic Cells by a PEGylated TLR7 Ligand for Treatment of Type 1 Diabetes

“…Prior reports have indicated that treatment with TLR ligands or TNFα could induce a suppressor phenotype in DC [39, 46–50]. Here, 1Z1 treated DC exhibited a semi-mature phenotype as indicated by surface activation markers including CD40, MHC class II, CD80 and CD86.…”

“…DC exposure to a TLR2 ligand enhanced CD4 + CD25 + Treg proliferation, and treatment of pre-diabetic mice with a synthetic TLR2 agonist diminished the onset of T1D, and increased the number and function of CD4 + CD25 + Treg [30, 38, 39]. Hence, involvement of Treg in the anti-inflammatory effect induced by 1Z1 in the NOD mice was studied to address whether 1Z1 directly stimulates Treg,…”

“…Activation of innate immune pathways by TLR ligands has been reported to inhibit progression of type 1 diabetes [30, 38, 39, 43, 50]. Recent data suggest that stimulation of TLRs can directly expand CD4 + CD25 + Treg that inhibit the onset or progression of autoimmune diseases [30, 36, 37, 38].…”

“…TLR agonists have been successfully used in NOD mice to delay T1D by inducing tolerogenic responses [38, 39, 50]. A major concern with the clinical application of TLR agonists is that exposure to a sufficiently high concentration of a TLR ligand might lead to an in vivo cytokine storm.…”

Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) modulates T1DM susceptibility by gut microbiota

“…These PRRs include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs). Interestingly, TLR deficiencies on the Non-Obese Diabetic (NOD) mouse background both increase susceptibility to and protect from T1DM [8][9][10][11][12][13]. Deficiency in MyD88, an adaptor protein that mediates most TLR signaling, induced complete protection from T1DM, which was abolished when MyD88 -/-NOD mice were housed in germ-free (GF)…”