Role of Interleukin-35 in sublingual allergy immunotherapy

Publication date: Available online 25 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Mohamed H. Shamji, Janice A. Layhadi, Daniela Achkova, Lubna Kouser, Alan Perera-Webb, Natália C. Couto-Francisco, Rebecca Parkin, Tomokazu Matsuoka, Guy Scadding, Philip G. Ashton-Rickardt, Stephen R. Durham

ABSTRACT

Background

Grass pollen-specific immunotherapy involves immunomodulation of allergen-specific T helper 2 cell (Th2) responses and induction of IL-10⁺ and/or TGF-β⁺CD4⁺CD25⁺ regulatory T cells (iTregs). IL-35⁺CD4⁺CD25⁺Foxp3^- T (iT_R35) cells have been reported as a novel subset of iTregs with modulatory characteristics.

Objective

To investigate the mechanisms underlying the induction and maintenance of immunological tolerance induced by IL-35 and iT_R35 cells.

Methods

The biological effects of IL-35 was assessed on Group II innate lymphoid cells (ILC2s), dendritic cells (DCs) primed with TSLP, IL-25 and IL-33, B and Th2 cells by flow cytometry and qRT-PCR. Grass pollen-driven Th2 cell proliferation and cytokine production was measured by [³H]-thymidine and Luminex MagPix, respectively. iTr35 cells were quantified in grass pollen allergics (SAR, n=16), sublingual immunotherapy-treated patients (SLIT, n=16) and non-atopic controls (NAC, n=16).

Results

SAR had elevated proportions of ILC2s (P=.002), IL5⁺ (P=.042), IL13⁺ (P=.042) and IL5⁺IL13⁺ILC2s (P=.003) compared to NAC. IL-35 inhibited IL-5 and IL-13 production by ILC2s in the presence of IL-25 or IL-33 (P=.031) and allergen-driven Th2 cytokines by T_eff cells. IL-35 inhibited CD40L, IL-4 and IL-21-mediated IgE production by B cells (P=.015), allergen-driven T cell proliferation (P=.001) and Th2 cytokine production by primed DCs. iT_R35 cells suppressed Th2 cell proliferation and cytokine production. In addition, allergen-driven IL-35 levels and iT_R35 cells were elevated in SLIT (all, P<.001) and NAC (all, P<.001) compared to SAR.

Conclusion

IL-35 and iT_R35 cells are potential novel immune-regulators induced by SLIT. The clinical relevance of SLIT may be underscored by the restoration of protective iT_R35 cells.

Graphical abstract

https://ift.tt/2LzLleQ