Toll-like Receptor 7 (TLR7) is a pattern recognition receptor located within the endosomes of immune cells, which can be activated by single-stranded RNA, or synthetic compounds called ‘imidazoquinolines’. A novel imidazoquinoline; GSK2245035; has been developed for use as an immunomodulatory agent in allergen-specific immunotherapy (AIT). In severe allergic disease to allergens such as Phleum pratense (Phlp), AIT is an effective curative regimen, although unmet needs remain regarding treatment duration and efficacy.
Grass pollen allergic patients were recruited for blood donations from which peripheral blood mononuclear cells (PBMCs) were used in an in vitro model of grass pollen allergy to assess the activity of the tool compound GSK2974932. Whole PBMCs and individual cell subsets including B cells, monocytes and T helper cells, were investigated by multi-parameter flow cytometry phenotyping as well as immunoassays to detect cytokine and immunoglobulin production.
Culture of PBMCs with GSK297 and Phlp allergen revealed significant suppression of TH2 cytokines IL-5 and IL-13. This suppression occurred in parallel with an upregulation of TH1-associated cytokines IL-12p70, IL-27, IFN-α2 and IFN-γ, as well as expanding the CXCR3+ TH1 cell population. Regulatory cytokines IL-10 and TGF-β1 were also increased. Isolated CD19+ B cells were found to be critical producers of GSK297 induced IL-10. GSK297 also induced activation of IL-10 secreting B regulatory cells and was capable of suppressing de novo IgE synthesis. Finally, depletion of CD19+ B cells and CD14+ Monocytes revealed a critical role in TLR7 mediated IL-10 and IL-27 induction.
In summary, this study has demonstrated that GSK297 is an effective immunomodulator in an in vitro proof of concept of study. It also proposes that TLR7 induced suppression of the allergic response to Phlp occurs through regulatory responses in the B cell compartment and enhancing TH1 cytokine production.