IDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes

Abstract

Originally predicated on the recognition of an increasing prevalence of allergy, the hygiene hypothesis was later found to accommodate the contrasting epidemiologic trends in developed countries for infectious vs autoimmune diseases. Experimentally, reduced exposure to infections will increase the risk of disease in several models of experimental autoimmunity. Although TLRs were initially considered as stimulatory molecules capable of activating early defense mechanisms against invading pathogens, emerging data suggest that they can also exert a regulatory function. In the present study, we evaluated whether TLR3 and TLR9, recognizing microbial dsDNA and CpG-containing DNA sequences, respectively, play a role in the protection from experimental autoimmune diabetes induced in C57BL/6 mice by streptozotocin. In wild-type animals, the disease was accompanied by up-regulation of IDO in pancreatic lymph nodes and would be greatly exacerbated by in vivo administration of an IDO inhibitor. Conversely, administration of a CpG-containing oligodeoxynucleotide greatly attenuated the disease in an IDO-dependent fashion. TLR9-, but not TLR3-deficient mice developed a more robust disease, an event accompanied by lack of IDO induction in pancreatic lymph nodes. Thus, our data suggest that the TLR9-IDO axis may represent a valuable target in the prevention/therapy of type 1 diabetes.

Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

“…In this regard, microbial products such as Complete Freund's Adjuvant or Toll-like receptor agonists are known to have dissimilar effects on diabetes depending on the model [1,2]. No studies with PyNTTTTGT ODNs and autoimmune diseases have been developed so far.…”

“…Extensive efforts have been directed towards the development of immunomodulatory treatments for maintaining and restoring beta cell mass [1,2].…”

High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

“…S1). As high-dosage CpG-ODN 1826 manifests pDC-dependent therapeutic activity in experimental autoimmunity 13 , we examined whether the higher concentration, 10 mg ml À 1 , of CpG-ODN would, in fact, confer tolerogenic activity on the pDCs. Cells were treated with 1 or 10 mg ml À 1 CpG-ODN, and admixed with spontaneously tolerogenic CD8 þ DCs (Fig.…”

“…TLR9 modulation of IDO1 is effective not only in the prevention and treatment of animal models of autoimmune 13 and allergic disorders 4,6,8 , but also in maintaining a physiological state of protective tolerance to ubiquitous fungal aeroantigens 36 . ABPA is a Th2-dependent hypersensitivity lung disease due to bronchial colonization of A. fumigatus that affects 1-2% of asthmatic and 7-9% of cystic fibrosis patients.…”

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

“…Nevertheless, tumors employ multiple means of suppressing or evading antitumor immunity [24] and cannot be overcome by the CpG ODN treatment alone. For example, the CpG ODN is a potent inducer of IL-10 from DCs and has been found to protect Streptozocin-induced autoimmune diabetes by the induction of IDO and Tregs [25] . Indeed, administration of the CpG ODN in the current study increased the frequency of NK and CTL cell infiltration, IFNγ secretion, and M1 cell differentiation but did not suppress the number of Tregs in the spleen.…”