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The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells

Background: Lenalidomide (LEN), an immunomodulatory drug (IMiD), is currently used for treatment of multiple myeloma (MM). LEN potentiates T cell and natural killer cell functions. However, the cellular and molecular mechanisms underlying the immunomodulatory effects of LEN remain unclear. We focuse...

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Autores principales: Kibata, Kayoko, Ito, Tomoki, Inaba, Muneo, Tanaka, Akihiro, Iwata, Ryoichi, Inagaki-Katashiba, Noriko, Phan, Vien, Satake, Atsushi, Nomura, Shosaku
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635835/
https://www.ncbi.nlm.nih.gov/pubmed/31372079
http://dx.doi.org/10.2147/JBM.S206459
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author Kibata, Kayoko
Ito, Tomoki
Inaba, Muneo
Tanaka, Akihiro
Iwata, Ryoichi
Inagaki-Katashiba, Noriko
Phan, Vien
Satake, Atsushi
Nomura, Shosaku
author_facet Kibata, Kayoko
Ito, Tomoki
Inaba, Muneo
Tanaka, Akihiro
Iwata, Ryoichi
Inagaki-Katashiba, Noriko
Phan, Vien
Satake, Atsushi
Nomura, Shosaku
author_sort Kibata, Kayoko
collection PubMed
description Background: Lenalidomide (LEN), an immunomodulatory drug (IMiD), is currently used for treatment of multiple myeloma (MM). LEN potentiates T cell and natural killer cell functions. However, the cellular and molecular mechanisms underlying the immunomodulatory effects of LEN remain unclear. We focused on the effects of LEN on human plasmacytoid dendritic cells (pDCs), which are the major source of interferon (IFN)-α in the blood and play a central role in innate immune responses. Results: We found that bortezomib, a proteasome inhibitor used to treat MM, killed pDCs but that 0.1–3 μM LEN (covering clinical plasma concentration range) did not affect pDC survival or CD86 expression. Bortezomib inhibited pDC-derived IFN-α production in a dose-dependent fashion, but 0.1–3 µM LEN sustained pDC-derived IFN-α production when stimulated with an optimal concentration of CpG-ODN 2216 (3 μM). In pDCs stimulated with a low concentration of CpG-ODN (0.1 μM), LEN enhanced IFN-α production. These results indicated that LEN, when used at a clinically relevant concentration, can potentially enhance IFN-α production by pDCs. Conclusion: Collectively, our findings unveiled a novel target of LEN and extend the repertoire of the drug’s known immunomodulatory effects. These effects may explain the low incidence of herpes zoster viral infection observed during LEN treatment compared with bortezomib treatment. LEN may function as an IMiD affecting a wide array of immune cells, including pDCs, leading to amplification of a positive immune axis able to eliminate MM cells.
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spelling pubmed-66358352019-08-01 The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells Kibata, Kayoko Ito, Tomoki Inaba, Muneo Tanaka, Akihiro Iwata, Ryoichi Inagaki-Katashiba, Noriko Phan, Vien Satake, Atsushi Nomura, Shosaku J Blood Med Original Research Background: Lenalidomide (LEN), an immunomodulatory drug (IMiD), is currently used for treatment of multiple myeloma (MM). LEN potentiates T cell and natural killer cell functions. However, the cellular and molecular mechanisms underlying the immunomodulatory effects of LEN remain unclear. We focused on the effects of LEN on human plasmacytoid dendritic cells (pDCs), which are the major source of interferon (IFN)-α in the blood and play a central role in innate immune responses. Results: We found that bortezomib, a proteasome inhibitor used to treat MM, killed pDCs but that 0.1–3 μM LEN (covering clinical plasma concentration range) did not affect pDC survival or CD86 expression. Bortezomib inhibited pDC-derived IFN-α production in a dose-dependent fashion, but 0.1–3 µM LEN sustained pDC-derived IFN-α production when stimulated with an optimal concentration of CpG-ODN 2216 (3 μM). In pDCs stimulated with a low concentration of CpG-ODN (0.1 μM), LEN enhanced IFN-α production. These results indicated that LEN, when used at a clinically relevant concentration, can potentially enhance IFN-α production by pDCs. Conclusion: Collectively, our findings unveiled a novel target of LEN and extend the repertoire of the drug’s known immunomodulatory effects. These effects may explain the low incidence of herpes zoster viral infection observed during LEN treatment compared with bortezomib treatment. LEN may function as an IMiD affecting a wide array of immune cells, including pDCs, leading to amplification of a positive immune axis able to eliminate MM cells. Dove 2019-07-12 /pmc/articles/PMC6635835/ /pubmed/31372079 http://dx.doi.org/10.2147/JBM.S206459 Text en © 2019 Kibata et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Kibata, Kayoko
Ito, Tomoki
Inaba, Muneo
Tanaka, Akihiro
Iwata, Ryoichi
Inagaki-Katashiba, Noriko
Phan, Vien
Satake, Atsushi
Nomura, Shosaku
The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
title The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
title_full The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
title_fullStr The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
title_full_unstemmed The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
title_short The immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
title_sort immunomodulatory-drug, lenalidomide, sustains and enhances interferon-α production by human plasmacytoid dendritic cells
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635835/
https://www.ncbi.nlm.nih.gov/pubmed/31372079
http://dx.doi.org/10.2147/JBM.S206459
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