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Type 1 diabetes (T1D) in NOD mouse models : the role of toll-like receptor 7 and an enteric bacterial pathogen in accelerating the development of T1D Lee, Andrew Seong-tae

Abstract

Enteric viruses, intestinal enteropathies and the subsequent activation of endosomal toll-like receptors (TLRs) have been implicated as triggers of type 1 diabetes (T1D). TLR7 detects single stranded RNA. TLR7 agonists can accelerate diabetes by enhancing islet expression of major histocompatibility complex (MHC) I restricted transgenic antigens but the role and source of TLR7 stimulation in promoting T1D (and reactivity to true self antigens) remains unclear. In addition, recent evidence has suggested that disruption of the intestinal barrier, a ‘leaky gut’, may provide an endogenous TLR source that drives the autoimmune response in T1D. We used non-obese diabetic (NOD) mouse models of human T1D to investigate the role of TLR7 activation and an enteric bacterial pathogen, Citrobacter rodentium, that disrupts the intestinal barrier integrity in the development of T1D. TLR7 activation with the imidazoquinoline CL097 in NOD mice caused the activation of bone marrow derived dendritic cells in vitro, the general activation of T and B cells in vivo, and the production of proinflammatory cytokines. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against IGRP (islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 and anti-CD40 compared to negative controls. This treatment combination accelerated the onset of T1D in NOD 8.3 T cell receptor (TCR) transgenic mice (8.3 NOD mice). This accelerated disease in 8.3 NOD mice was significantly delayed when TLR7 signaling was blocked using the oligodeoxynucleotide (ODN) inhibitor, IRS661. Pre-diabetic (12-week) NOD mice displayed increased intestinal barrier permeability when compared to C57BL/6 and diabetes resistant NOR mice. Moreover, the development of invasive insulitis is accelerated when young (4-week) NOD mice are infected with C. rodentium. C. rodentium infected NOD mice demonstrate increased colonic permeability, increased activation of polyclonal and diabetogenic cytotoxic T lymphocytes (CTLs) and increased C. rodentium counts in the mesenteric and pancreatic lymph nodes, compared to uninfected NOD mice. Taken together, these findings demonstrate that TLR7 signaling can modulate the development of T1D and an enteric bacterial pathogen can modulate the development of invasive insulitis. Thus, TLR7 antagonism and maintaining an intact intestinal barrier may provide distinct therapeutic approaches in preventing the development of T1D.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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