Induction of human allergen-specific immune regulation following treatment with a combination of Toll-Like Receptor 7 agonist with allergen: an in vit

Allergic rhinitis and asthma result from aberrant Th2-type immune reactivity against common inhaled allergens. Existing therapies alleviate symptomatology, but do not offer alteration of disease progress. The only therapeutic modality that has been associated with the development of immune tolerance to allergens and modification of underlying disease pathophysiology is allergen specific immunotherapy. However, allergen immunotherapy has several limitations, including the need of regular administration for several years, that restrict its effectiveness and broad application. To improve its efficacy and dosing regimen co-administration with immunopotentiators capable of promoting in a controlled fashion, the generation of Th1 and/or regulatory T and B cell responses has been proposed.

This research study is designed to examine whether stimulation of the Toll-like receptor 7 (TLR7) immune cascade, using selective ligands developed by GSK, can modulate the phenotype of human allergen-specific Th2 immune response and enhance counter-regulatory immune mechanisms, rendering such molecules valid candidates for adjuvants of allergen immunotherapy. Early assessment of the biological activity of the selective TLR7 ligand GSK2245035 has shown preferential induction of IFN-a over TNF-a and a promising pharmacological profile for human use. In this study, the effect of treatment of blood mononuclear cells from grass allergic patients with the TLR7 agonist and grass allergen will be evaluated, in terms of proliferation, cytokine generation and induction of Th cell phenotype. If a shift in the allergen-driven Th2 cytokine production (reduction>50%) is observed, detailed analysis of the mechanisms mediating it will be pursued. In particular the effect of treatment with TLR7 agonist on dendritic cells and monocytes will be examined, as well as how this modulates subsequent new and memory allergen-specific Th cell responses will be analyzed using human APC- T cells co-culture systems. Additionally, the potential generation of functional IL-10 producing regulatory B cells will be explored. In parallel, the effect of the TLR7 agonist on human nasal epithelial cells will be assessed to determine whether it can influence the priming of allergen-specific immune responses.

If the results from these studies indicate an effect associated with suppression of allergen-stimulated Th2-like responses, an experimental medicine study, using a nasal allergen challenge model, will be planned to assess whether intranasal administration of GSK224535, together with an adjusted short course of allergen immunotherapy facilitates the induction of allergen desensitisation in patients with grass-pollen allergic rhinitis.