Early IL-10 producing B-cells and coinciding Th/Tr17 shifts during three year grass-pollen AIT

October 2018Volume 36, Pages 475–488

Ulrich M. Zissler1

, 

Constanze A. Jakwerth1

, 

Ferdinand M. Guerth

, 

Lisa Pechtold

, 

Juan Antonio Aguilar-Pimentel

, 

Katharina Dietz

, 

Kathrin Suttner

, 

Guido Piontek

, 

Bernhard Haller

, 

Zuzana Hajdu

, 

Matthias Schiemann

, 

Carsten B. Schmidt-Weber

, 

Adam M. ChakerCorrespondence information about the author Adam M. ChakerEmail the author Adam M. Chaker

Open Access

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DOI: https://doi.org/10.1016/j.ebiom.2018.09.016

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Abstract

Background

Allergen-specific immunotherapy (AIT) is a causative treatment in allergic airway disease, comprising long-term allergen administration and requiring three years of treatment. Mechanisms and biomarkers that translate into clinical efficacy remain urgently needed.

Methods

In an exploratory observational allergy cohort we phenotyped 32 grass-pollen allergic patients with hayfever undergoing AIT for over three years and controls using local and systemic samples for ex vivo FACS, nasal transcriptomes and in vitro phleum-stimulation at critical time windows six hours after therapeutic allergen administration and during peak-season responses.

Findings

The up-dosing phase is marked by increased IL-10+ B-cells with allergen-specific PD-L1 up-regulation, while effector Th1/Th17 cells and CCR6+IL-17+FoxP3+T-cells decrease. The conversion phase exhibits Th17 recovery in the absence of Th2 cells. The tolerance-mounting phase after three years of treatment is characterized by induction of Tregs while Th2 and phleum-specific Th17 responses decrease. Notably, high ratios of circulating Breg/Th17 following initial AIT correlate significantly with clinical improvement after three years.

Interpretation

Our exploratory data hypothezise differential shifts in the hierarchy of tolerance in three distinct phases of AIT characterized by conversion of regulatory against pro-inflammatory mechanisms, of which the Breg/Th17 ratio after initial treatment emerges as potential early prediction of AIT efficacy.

Fund

This study was partially funded by Allergopharma GmbH & Co. KG, intramural funding and the German Center for Lung Research (DZL).

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