Tolerogenic dendritic cells attenuate experimental autoimmune antimyeloperoxidase glomerulonephritis

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Abstract

Background Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO). Methods We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFkB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti–methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells. Results MPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10–producing regulatory T cells in MPO-immunized mice without affecting IL-10+ CD4+Foxp32 type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4+Foxp3+ cells were depleted in vivo, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4+Foxp32 or CD4+Foxp3+ cells showed that MPO/BAY dendritic cells generate Foxp3+ regulatory T cells from CD4+Foxp32 cells through several pathways, and induce IL-10+ regulatory T cells via inducible costimulator (ICOS), which was confirmed in vivo. Transfer of MPO/BAY dendritic cell–induced regulatory T cells in vivo, with or without anti–IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN via IL-10. Conclusions MPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10–expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.

Original languageEnglish
Pages (from-to)2140-2157
Number of pages18
JournalJournal of the American Society of Nephrology
Volume30
Issue number11
DOIs
Publication statusPublished - Nov 2019

Cite this

@article{d317d5e8622b49e495062569952a5233,
title = "Tolerogenic dendritic cells attenuate experimental autoimmune antimyeloperoxidase glomerulonephritis",
abstract = "Background Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO). Methods We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFkB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti–methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells. Results MPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10–producing regulatory T cells in MPO-immunized mice without affecting IL-10+ CD4+Foxp32 type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4+Foxp3+ cells were depleted in vivo, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4+Foxp32 or CD4+Foxp3+ cells showed that MPO/BAY dendritic cells generate Foxp3+ regulatory T cells from CD4+Foxp32 cells through several pathways, and induce IL-10+ regulatory T cells via inducible costimulator (ICOS), which was confirmed in vivo. Transfer of MPO/BAY dendritic cell–induced regulatory T cells in vivo, with or without anti–IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN via IL-10. Conclusions MPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10–expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.",
author = "Dragana Odobasic and Virginie Oudin and Kenji Ito and Gan, {Poh Yi} and {Richard Kitching}, A. and Holdsworth, {Stephen R.}",
year = "2019",
month = "11",
doi = "10.1681/ASN.2019030236",
language = "English",
volume = "30",
pages = "2140--2157",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
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}

Tolerogenic dendritic cells attenuate experimental autoimmune antimyeloperoxidase glomerulonephritis. / Odobasic, Dragana; Oudin, Virginie; Ito, Kenji; Gan, Poh Yi; Richard Kitching, A.; Holdsworth, Stephen R.

In: Journal of the American Society of Nephrology, Vol. 30, No. 11, 11.2019, p. 2140-2157.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Tolerogenic dendritic cells attenuate experimental autoimmune antimyeloperoxidase glomerulonephritis

AU - Odobasic, Dragana

AU - Oudin, Virginie

AU - Ito, Kenji

AU - Gan, Poh Yi

AU - Richard Kitching, A.

AU - Holdsworth, Stephen R.

PY - 2019/11

Y1 - 2019/11

N2 - Background Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO). Methods We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFkB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti–methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells. Results MPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10–producing regulatory T cells in MPO-immunized mice without affecting IL-10+ CD4+Foxp32 type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4+Foxp3+ cells were depleted in vivo, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4+Foxp32 or CD4+Foxp3+ cells showed that MPO/BAY dendritic cells generate Foxp3+ regulatory T cells from CD4+Foxp32 cells through several pathways, and induce IL-10+ regulatory T cells via inducible costimulator (ICOS), which was confirmed in vivo. Transfer of MPO/BAY dendritic cell–induced regulatory T cells in vivo, with or without anti–IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN via IL-10. Conclusions MPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10–expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.

AB - Background Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO). Methods We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFkB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti–methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells. Results MPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10–producing regulatory T cells in MPO-immunized mice without affecting IL-10+ CD4+Foxp32 type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4+Foxp3+ cells were depleted in vivo, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4+Foxp32 or CD4+Foxp3+ cells showed that MPO/BAY dendritic cells generate Foxp3+ regulatory T cells from CD4+Foxp32 cells through several pathways, and induce IL-10+ regulatory T cells via inducible costimulator (ICOS), which was confirmed in vivo. Transfer of MPO/BAY dendritic cell–induced regulatory T cells in vivo, with or without anti–IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN via IL-10. Conclusions MPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10–expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.

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U2 - 10.1681/ASN.2019030236

DO - 10.1681/ASN.2019030236

M3 - Article

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JO - Journal of the American Society of Nephrology

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SN - 1046-6673

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