Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

Leaker, Brian R.; Singh, Dave; Lindgren, Sam; Almqvist, Gun; Eriksson, Leif; Young, Barbara; O’Connor, Brian

The cellular and molecular mechanisms by which a brief intranasal exposure of a TLR7 agonist can produce long-term immune effects in the lung remain speculative although the united airways hypothesis may be involved. The precise mechanism by which TLR7 agonists abrogate the LAR in allergic asthmatics also remains to be elucidated. It is possible that antigen presenting cells such as dendritic cells [40] or certain macrophages (e.g. M2 subtypes) [41, 42] may traffic to lymph nodes after exogenous exposure in the nose. Alternatively, innate lymphoid cells may be involved. Of the three sub-types of ILC, ILC2 may be involved in generating Th2 responses when activated by epithelial-derived cytokines such as thymic stromal lymphopoietin (TSLP), whereas ILC1 type cells may be stimulated by TLR7 agonists to reverse this trend towards the Th2 asthma phenotype by releasing IFNγ. TSLP appears to be an important common pathway between airway epithelium and inflammatory cascades [43, 44] and counts of ILC1 cells, such as NK cells, have been found to be low in patients with severe asthma [45] . TLR7 activation induces transcription of NF-κB [46] with induction of an innate immune response; typically production of IFNγ and pro-inflammatory cytokines (IL-1β). The upregulation of Th1 responses may alter the Th1 versus Th2 [47] immune state in susceptible asthma subjects and result in abrogation of allergic Th2 responses induced by allergen [48] . Nevertheless, in this study the effects of AZD8848, whilst persisting for 1 week beyond the end of dosing, were not sustained for the relatively longer period seen in rodent models. Direct stimulation of TLR7 in the lung itself may be needed to effect such a sustained change in the immune response. It remains to be established whether administration of AZD8848 directly to the human lung might induce an effect equivalent in magnitude and duration to that seen in rodent models of inflammatory disease.