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Dendritic cells generated in the presence of interferon-α and modulated with dexamethasone as a novel tolerogenic vaccine platform

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Abstract

Background

Tolerogenic dendritic cells (tDCs) are considered a novel therapeutic tool in treating autoimmune diseases, allergies, and transplantation reactions. Among numerous pharmacological immune modulators, dexamethasone (Dex) is known to induce potent tolerogenicity in DCs generated from human monocytes with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), and these cells (IL-4-DCs/Dex) are being appraised as a tDC-based platform in clinical settings. Interferon-α (IFNα) represents another powerful inducer of monocyte-derived DCs, which possess higher migratory activity and stability. However, the functions of IFN-DCs/Dex have not been sufficiently analyzed and there are no comparative studies of the tolerogenicity of IFN-DCs/Dex and IL-4-DCs/Dex. This study aimed to investigate the properties of IFN-DCs/Dex in comparison with IL-4-DCs/Dex.

Results

DCs were obtained by cultivation of an adherent fraction of peripheral blood mononuclear cells (MNCs) in the presence of GM-CSF and IFNα or IL-4 with subsequent lipopolysaccharide-driven maturation. Dex (10−6 M) was added to the cultures at day 3. We showed that generation of IFN-DCs with Dex resulted in decrease in percentage of CD83+ and CD86+ DCs and increase in numbers of CD14+, B7-H1+, and Toll-like receptor 2 (TLR2+) DCs. Treatment with Dex downregulated pro-inflammatory cytokine production, reduced DC allostimulatory activity, and inhibited DC capacity to stimulate Th1/pro-inflammatory cytokine production, altogether evidencing the induction of a tolerogenic phenotype. As compared to IL-4-DCs/Dex, IFN-DCs/Dex were characterized by larger proportion of TLR2+ and CD14+ cells, higher production of IL-10 and lower TNFα/IL-10 ratio, more potent capacity to induce T cell anergy, and more efficiently skewed T cell cytokine balance towards Th2/anti‐inflammatory profile.

Conclusions

The data obtained indicate that potent tDCs could be generated by treating IFN-DCs with dexamethasone. The tolerogenic properties of IFN-DCs/Dex are better than or at least equal to those of the IL-4-DCs/Dex, as assessed by in vitro phenotypic and functional assays, suggesting these cells as a new tolerogenic vaccine platform.

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Abbreviations

DCs:

Dendritic cells

Dex:

Dexamethasone

IFN-DCs:

Interferon-α-induced DCs

IL-4-DCs:

Interleukin-4-induced DCs

MLR:

Mixed leukocyte reactions

MNCs:

Mononuclear cells

tDCs:

Tolerogenic dendritic cells

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Acknowledgements

The authors thank A. Delvig for a professional language editing service.

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Authors and Affiliations

  1. Research Institute of Fundamental and Clinical Immunology, Yadrintsevskaya Str., 14, Novosibirsk, Russian Federation, 630099

    Olga Leplina, Yulia Kurochkina, Marina Tikhonova, Ekaterina Shevela, Alexandr Ostanin & Elena Chernykh

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  1. Olga Leplina
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  2. Yulia Kurochkina
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  3. Marina Tikhonova
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  4. Ekaterina Shevela
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  5. Alexandr Ostanin
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  6. Elena Chernykh
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Correspondence to Olga Leplina.

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The authors declare that they have no competing interests.

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Our research involved whole blood samples from healthy donors after receiving written informed consent. The study was approved by the Ethics Committee of the Institute of Fundamental and Clinical Immunology on March 14, 2017.

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Leplina, O., Kurochkina, Y., Tikhonova, M. et al. Dendritic cells generated in the presence of interferon-α and modulated with dexamethasone as a novel tolerogenic vaccine platform. Inflammopharmacol 28, 311–319 (2020). https://doi.org/10.1007/s10787-019-00641-1

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  • DOI: https://doi.org/10.1007/s10787-019-00641-1

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