Immunization with an adenovirus-vectored TB vaccine containing Ag85A-Mtb32 effectively alleviates allergic asthma

Yiling Zhang,Kefang Lai,Xiang Gao,Xianmiao Ye,Pingchao Li,Na Li,Zhong Su,Liang Li,Baoqing Sun,Qian Wang,Ying Feng,Xuehua Zheng,Ling Chen,Liqiang Feng,Chufang Li,Jinlin Wang,Nanshan Zhong,Feng Li

doi:10.1007/s00109-017-1614-5

Abstract

Current treatments for allergic asthma primarily ameliorate symptoms rather than inhibit disease progression. Regulating the excessive T helper type 2 (Th2) responses may prevent asthma exacerbation. In this study, we investigated the protective effects of Ad5-gsgAM, an adenovirus vector carrying two mycobacterial antigens Ag85A and Mtb32, against allergic asthma. Using an ovalbumin (OVA)-induced asthmatic mouse model, we found that Ad5-gsgAM elicited much more Th1-biased CD4+T and CD8+T cells than bacillus Calmette-Guérin (BCG). After OVA challenge, Ad5-gsgAM-immunized mice showed significantly lowered airway inflammation in comparison with mice immunized with or without BCG. Total serum immunoglobulin E and pulmonary inducible-nitric-oxide-synthase were efficiently reduced. The cytokine profiles in bronchial-alveolar-lavage-fluids (BALFs) were also modulated, as evidenced by the increased level of interferon-γ (IFN-γ) and the decreased level of interleukin (IL)-4, IL-5, and IL-13. Anti-inflammatory cytokine IL-10 was sharply increased, whereas pro-inflammatory cytokine IL-33 was significantly decreased. Importantly, exogenous IL-33 abrogated the protective effects of Ad5-gsgAM, revealing that the suppression of IL-33/ST2 axis substantially contributed to protection against allergic inflammation. Moreover, regulatory T cells were essential for regulating aberrant Th2 responses as well as IL-33/ST2 axis. These results suggested that modulating the IL-33/ST2 axis via adenovirus-vectored mycobacterial antigen vaccination may provide clinical benefits in allergic inflammatory airways disease.Key messages•Ad5-gsgAM elicits Th1 responses and suppresses Th2-mediated allergic asthma in mice.•Ad5-gsgAM inhibits IL-33/ST2 axis by reducing IL-33 secretion but not ILC2 recruiting.•Treg is essential for modulating Th2 responses and IL-33/ST2 axis by Ad5-gsgAM.

Highlights

Asthma is a complex syndrome characterized by airway hyperresponsiveness (AHR), airflow obstruction, and airway infiltration of inflammatory cells, which affects 5–16% of people worldwide [1]
The frequencies of IFN-γ+CD4+T and IFN-γ+CD8+T cells were much higher in Ad5-gsgAM-immunized mice than in bacillus CalmetteGuérin (BCG)-immunized mice (Fig. 1a–d), suggesting that Ag85A and Mtb32 have strong immunogenicity when harbored in an adenovirus vector
When stimulated with Phorbol 12-myristate-13-acetate (PMA) and ionomycin, much more IFN-γ-producing CD4+T and CD8+T cells were observed in Ad5-gsgAM-immunized mice than in BCG- or Ad5-immunized mice (Fig. S1c–f)

Summary

Introduction

Asthma is a complex syndrome characterized by airway hyperresponsiveness (AHR), airflow obstruction, and airway infiltration of inflammatory cells, which affects 5–16% of people worldwide [1]. The treatments available mainly depend on inhaled corticosteroids and sometimes in combination with long-acting beta agonists [1]. These treatments, which are usually administrated as life-long daily medications, only control symptoms but not inhibit disease progression [1]. A single antibody only shows moderate, if any, benefits in patients with severe asthma or in particular subgroups [3]. Adverse effects such as immuno-suppression are observed [2, 4, 5]. Novel approaches, which can reduce and even prevent asthma exacerbation, are urgently needed

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Conclusion