Imidazoquinoline Acts as Immune Adjuvant for Functional Alteration of Thymic Stromal Lymphopoietin-Mediated Allergic T Cell Response

Abstract

Atopic dermatitis is a major allergic disease that develops through dysregulation of Th2-mediated inflammation. Although dendritic cells (DCs) have been thought to play a critical role in the upstream phase of the allergic cascade, conventional drugs such as steroids and chemical mediator antagonists target the effector cells or factors in allergic inflammation. Recently, it has been demonstrated that interaction between thymic stromal lymphopoietin (TSLP) and human DCs plays an essential role in evoking inflammatory Th2 responses in allergy through OX40 ligand expression on DCs. In this study, we provide evidence that R848, an imidazoquinoline compound, which is a TLR ligand and a strong Th1 response-inducing reagent, is a potent adjuvant for the alteration of the Th2-inducing potency of human DCs activated by TSLP (TSLP-DCs). R848 inhibited the inflammatory Th2-inducing capacity of TSLP-DCs and redirected them to possessing an IL-10 and IFN-γ-producing regulatory Th1-inducing capacity. This functional alteration depended on both repression of OX40 ligand expression and induction of IL-12 production from DCs by the addition of R848. Additionally, R848 had the ability to inhibit the TSLP-mediated expansion and maintenance of the Th2 memory response. These findings suggest that imidazoquinoline may be a useful in the treatment of allergic diseases that are triggered by TSLP.

Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

“…71 This was mainly based on a higher induction of IL-10-and IFN-g-producing regulatory T-cell subtypes by those DCs. 72 Another TLR ligand, the TLR7/TLR8 agonist imidazoquinoline has been demonstrated to inhibit the TSLP-mediated T H 2 immune responses inducing properties of DCs in vitro. 72 Consequently, the protective effect of this TLR agonist on allergic immune responses might be useful for the treatment of atopic disorders in vivo.…”

Cellular and Molecular Mechanisms of TSLP Function in Human Allergic Disorders - TSLP Programs the “Th2 code” in Dendritic Cells

“…77–79 Both agents could function as potent inhibitors of OX40L expression on human DCs, while they induce IL-12 production by DCs, even in the presence of TSLP. 80,81 As a result, they could cancel the DC-mediated Th2-permissive condition and in turn induce the generation of IL-10 + IFN-γ + regulatory Th1 cells. 80,81 This type of Th1-like T cells has been reported to possess the ability to inhibit airway hyperresponsiveness.…”

“…80,81 As a result, they could cancel the DC-mediated Th2-permissive condition and in turn induce the generation of IL-10 + IFN-γ + regulatory Th1 cells. 80,81 This type of Th1-like T cells has been reported to possess the ability to inhibit airway hyperresponsiveness. 82 Moreover, imidazoquinoline can block the functional characteristics of CRTH2 + CD4 + Th2 memory cells that are expanded and maintained by TSLP-DCs.…”

“…82 Moreover, imidazoquinoline can block the functional characteristics of CRTH2 + CD4 + Th2 memory cells that are expanded and maintained by TSLP-DCs. 81 In terms of signal transduction of TSLP in DCs, a JAK inhibitor clearly shut down the TSLP-dependent signals. 70 Thus, using a JAK inhibitor for treatment of allergic diseases proposed recently 83 might also dampen the TSLP signal transduction, leading to alleviation of disease symptoms.…”

Plasmacytoid DCs, exposed to TSLP in synergy with TLR ligands, acquire significant potential towards Th2 polarization

“…Such triggers and modifiers, particularly on mucosal sites, might be represented by infection and therefore engagement of TLR ligands. Several reports were recently published on the role of infection-induced TSLP and its influence on DCs and subsequent immune response [14,15]. …”