title: Treatment with the TLR7 agonist R848 induces regulatory T-cell-mediated suppression of established asthma symptoms.
abstract: The evolution of allergic asthma is tightly controlled by effector and regulatory cells, as well as cytokines such as IL-10 and/or TGF-β, and it is widely acknowledged that environmental exposure to allergens and infectious agents can influence these processes. In this context, the recognition of pathogen-associated motifs, which trigger TLR activation pathways, plays a critical role with important consequences for disease progression and outcome. We addressed the question whether the TLR7 ligand resiquimod (R848), which has been shown to be protective in several experimental allergic asthma protocols, can also suppress typical asthma symptoms once the disease is established. To this end, we used an OVA-induced experimental model of murine allergic asthma in which R848 was injected after a series of challenges with aerosolized OVA. We found that the treatment attenuated allergic symptoms through a mechanism that required Tregs, as assessed by the expansion of this population in the lungs of mice having received R848, and the loss of R848-mediated suppression of allergic responses after in vivo Treg depletion. IL-10 provided only a minor contribution to this suppressive effect that was largely mediated through a TGF-β-dependent pathway, a finding that opens new therapeutic opportunities for the pharmacological targeting of Tregs.
authors.affiliation: Université Paris Descartes, Hôpital Necker, Paris, France.
authors.forename: Linh Pham
authors.initials: LP
authors.lastname: Van
authors.forename: Emilie
authors.initials: E
authors.lastname: Bardel
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gregoire
authors.forename: Jeroen
authors.initials: J
authors.lastname: Vanoirbeek
authors.forename: Elke
authors.initials: E
authors.lastname: Schneider
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thieblemont
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology; D008168:Lung / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D007093:Imidazoles; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D010047:Ovalbumin; C402365:resiquimod