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IDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes¹

Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Associazione per l’Aiuto ai Giovani con Diabete dell’Umbria (to U.G.).

² F.F. and C.V. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Ursula Grohmann, Department of Experimental Medicine and Biochemical Sciences, Via del Giochetto, 06126 Perugia, Italy. E-mail address: ugrohmann{at}tin.it

⁴ Abbreviations used in this paper: T1D, type 1 diabetes; 1-MT, 1-methyl-DL-tryptophan; DC, dendritic cell; IKK, IB kinase; ODN, oligodeoxynucleotide; pDC, plasmacytoid DC; PLN, pancreatic lymph node; SPF, specific pathogen free; STZ, streptozotocin; Treg, T regulatory; WT, wild type.