Toll-like receptor 7-triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma.
BACKGROUND
Toll-like receptor (TLR) 7/8 ligands are promising candidate drugs for the treatment of allergic asthma and rhinitis. Although their clinical application depends on the development of strategies for topical administration to the lung, this has not been explored in preclinical disease models.


OBJECTIVE
To examine the therapeutic effectiveness, persistence of effect, and mode of action of intranasal TLR7 ligand administration in allergic airway disease.


METHODS
Wild-type, IFN-alpha receptor (IFN-alphaR)(-/-), IFN-gamma(-/-), CD8(-/-), TLR7(-/-), and radiation-induced chimeric mice deficient in hematopoietic TLR7 expression were subjected to an established model of allergic airway disease. R-848, a specific TLR7 agonist in mice, was administered prophylactically or therapeutically and effects of treatment on helper T-cell type 2 (Th2) responses, eosinophilia, goblet cell metaplasia, and airway hyperresponsiveness were assessed.


RESULTS
Intranasal R-848 administration induced a transient immune response characterized by type I interferon production and infiltration of innate immune cells into the lung. This conferred long-term suppression of allergic airway disease via two complementary molecular processes, one mediated by type I interferons and providing acute protection by directly inhibiting effector Th2 responses, and one mediated by immunoregulatory CD8(+) T cells and inducing long-lasting protection by suppressing Th2 responses in an IFN-gamma-dependent manner.


CONCLUSIONS
Intranasal R-848 administration is an effective treatment for allergic airway disease. It hijacks an otherwise proinflammatory immune process triggered by TLR7 to mediate long-lasting disease suppression. This provides important insight into the efficacy and mode of action of TLR7 ligands in murine models of allergic airway disease and paves the way for their clinical application in humans.
Center for Immunology and Transplantation, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece.
Charoula
C
Xirakia
Ourania
O
Koltsida
Athanasios
A
Stavropoulos
Artemis
A
Thanassopoulou
Vassilis
V
Aidinis
Paschalis
P
Sideras
Evangelos
E
Andreakos
D000281:Administration, Intranasal; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D056747:Immunomodulation; D007372:Interferons / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018418:Th2 Cells / Q000378:metabolism; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D015854:Up-Regulation
D016207:Cytokines; D007093:Imidazoles; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D007372:Interferons; C402365:resiquimod