Inhibition of experimental asthma by indoleamine 2,3-dioxygenase

Abstract

Epidemiological evidence points to the inverse relationship between microbial exposure and the prevalence of allergic asthma and autoimmune diseases in Westernized countries. The molecular basis for this observation has not yet been completely delineated. Here we report that the administration of certain toll-like receptor (TLR) ligands, via the activation of innate immunity, induces high levels of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism in various organs. TLR9 ligand-induced pulmonary IDO activity inhibits Th2-driven experimental asthma. IDO activity expressed by resident lung cells rather than by pulmonary DCs suppressed lung inflammation and airway hyperreactivity. Our results provide a mechanistic insight into the various formulations of the hygiene hypothesis and underscore the notion that activation of innate immunity can inhibit adaptive Th cell responses.

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

“…17,49,50 Although TLR activation can promote Th2-type allergic inflammation, 51 targeting TLR9 with CpG has proved to be a highly effective therapeutic approach in experimental asthma. 52 The containment of Aspergillus in the allergic host requires TLR9 expression, 30 and exogenous CpG reverses fungal asthma when administered at a dose of 50 g for 2 weeks by intranasal, but not i.p., injection. 8 CpG given in this manner has caused tumor necrosis factor-␣-dependent toxicity in rodents.…”

On watching the watchers: IDO and type I/II IFN

“…In most of these models, the protective function of pDC and the associated type I IFN response appears to be an intrinsic ability of the system to co-activate cytostatic mechanisms, induce the death of effector Th2 cells, or polarize T cells towards an IL-10-producing Treg phenotype [3,4,10,13].…”

“…At the same, tryptophan catabolism appears to fulfill all the requirements to initiate the above-mentioned effects, including T cell proliferation arrest [2], induction of Th2 cell apoptosis [1], reversible impairment of T cell function through down-regulation of the TCR f chain [12], and the generation of IL-10-producing Treg cells [12]. Utilising the TLR9-dependent modulation of tryptophan catabolism could represent a novel therapeutic approach in the treatment of allergy and allergic inflammation [3,7].…”

“…Traditionally recognized for its role in infection, pregnancy, transplantation, autoimmunity and neoplasia [1,2], the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) has been found to have unexpected potential in the control of inflammation, allergy, and allergic airway inflammation [3], all conditions in which plasmacytoid DC (pDC) may have a protective function [4]. Some of the IDO-dependent effects are initiated by CpG-rich oligodeoxynucleotides (ODN) and rely on cell signaling through TLR9 [3,[5][6][7], whose activation typically results in type I IFN release by pDC [8].…”

“…Some of the IDO-dependent effects are initiated by CpG-rich oligodeoxynucleotides (ODN) and rely on cell signaling through TLR9 [3,[5][6][7], whose activation typically results in type I IFN release by pDC [8].…”