Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice

Abstract

BackgroundInfections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR) stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity.Methods and FindingsHere, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA)-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD) that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists.Conclusions/SignificanceThese observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies.

Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity

“…Another study performed by Aumeunier et al [153] on the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental non-obese diabetes (Fig. 3).…”

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

“…This suggests that repeated topical application of TLR7 agonists should be performed with caution in individuals at risk for autoimmune disease. Repeated high doses of parenteral TLR7 agonist prevent diabetes in NOD mice [41]. However, the relevance of repeated high-dose stimulation of TLR7 to human disease is unclear.…”

Echovirus Epidemics, Autoimmunity, and Type 1 Diabetes

“…These cells, instead of exerting effector functions such as killing infected cells or inducing interferon production, can turn off immune responses. The increment in TGF-concentrations induced by the viral infection is associated with Treg invigoration (Aumeunier et al, 2010;von Herrath, 2009). Other cytokines induced simultaneously are the programmed cell death ligand 1 (PD-1L) and the tumor necrosis factor (TNF)-which in turn may mediate the bystander death of auto-aggressive T-cells.…”