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Amino Acids. 2020 Feb 1. doi: 10.1007/s00726-020-02817-4. [Epub ahead of print]

Inhibition of antigen-specific immune responses by co-application of an indoleamine 2,3-dioxygenase (IDO)-encoding vector requires antigen transgene expression focused on dendritic cells.

Author information

1
Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
2
Ganzimmun Diagnostics AG, Mainz, Germany.
3
III. Medical Department, Asthma Core Facility, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
4
Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
5
Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. mbros@uni-mainz.de.

Abstract

We have previously shown that particle-mediated epidermal delivery (PMED) of plasmids encoding β-galactosidase (βGal) under control of the fascin-1 promoter (pFascin-βGal) yielded selective production of the protein in skin dendritic cells (DCs), and suppressed Th2 responses in a mouse model of type I allergy by inducing Th1/Tc1 cells. However, intranasal challenge of mice immunized with pFascin-βGal induced airway hyperreactivity (AHR) and neutrophilic inflammation in the lung. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in immune suppression and tolerance induction. Here we investigated the consequences of co-application of an IDO-encoding vector on the modulatory effect of DNA vaccination by PMED using pFascin-βGal in models of eosinophilic allergic and non-eosinophilic intrinsic airway inflammation. IDO-encoding plasmids and pFascin-βGal or pCMV-βGal were co-applied to abdominal skin of BALB/c mice without, before or after sensitization with βGal protein. Immune responses in the lung were analysed after intranasal provocation and airway reactivity was determined by whole body plethysmography. Co-application of pCMV-IDO with pFascin-βGal, but not pCMV-βGal inhibited the Th1/Tc1 immune response after PMED. Moreover, AHR in those mice was attenuated following intranasal challenge. Therapeutic vaccination of βGal-sensitized mice with pFascin-βGal plus pCMV-IDO slightly suppressed airway inflammation and AHR after provocation with βGal protein, while prophylactic vaccination was not effective. Altogether, our data suggest that only the combination of DC-restricted antigen and ubiquitous IDO expression attenuated asthma responses in mice, most probably by forming a tryptophan-depleted and kynurenine-enriched micromilieu known to affect neutrophils and T cells.

KEYWORDS:

Allergic airway inflammation; DNA vaccination; Dendritic cells; Fascin promoter; Indoleamine 2,3-dioxygenase (IDO); Particle-mediated epidermal delivery (PMED)

PMID:
32008091
DOI:
10.1007/s00726-020-02817-4

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