Mechanism of long-lasting suppression against Th2 immune response in the lung by a novel antedrug TLR7 agonist

Rationale: To identify the mechanisms by which a novel antedrug Toll like receptor 7 (TLR7) agonist, AZ12441970, mediates the long-lasting suppression of Th2 immune responses. Methods: Long-lasting efficacy of AZ12441970 against bronchoalveolar lavage (BAL) eosinophilia was investigated utilizing Ovalbumin (OVA)/Alum-sensitised mice or OVA-specific Th2 cells adoptively transferred into mice. The mechanism by which AZ12441970 mediated long-lasting efficacy was investigated utilizing T cell-deficient nude mice and several knock-out (KO) mice including type I IFN receptor KO mice, B cell KO mice and rag2 KO mice lacking B and T cells. Results: Weekly lung doses of AZ12441970 for 6 weeks significantly inhibited BAL eosinophilia for at least 6 weeks following cessation of dosing. The long-lasting efficacy observed with the compound was largely abolished in type I IFN receptor KO mice, rag2 KO mice or nude mice, but maintained in B cell KO mice. T cells were shown to be involved in the mechanism of efficacy in a T cell reconstituted nude mouse model of allergic airways inflammation. Nose only exposure of AZ12441970 also resulted in long-term efficacy in the lung. Conclusions: We show that intranasal dosing of AZ12441970 to achieve lung exposure in mice induces a long-lasting efficacy against Th2 immune responses in the lung. The efficacy in the lung is also achieved by nose only exposure of the TLR7 agonist. Furthermore, our mechanism studies demonstrate that the long-lasting inhibition of the Th2 immune responses with the compound is IFN-α- and T-cell-dependent. These data suggest that novel antedrug TLR7 agonists may have potential in the treatment of allergic disease.