Tolerogenic Dendritic Cells Attenuate Experimental Autoimmune Antimyeloperoxidase Glomerulonephritis.

Abstract

<b>Background</b> 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). We sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NF<i>κ</i>B 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. 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⁺Foxp3^- 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 <i>in vivo</i>, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4⁺Foxp3^- or CD4⁺Foxp3⁺ cells showed that MPO/BAY dendritic cells generate Foxp3⁺ regulatory T cells from CD4⁺Foxp3^- cells through several pathways, and induce IL-10⁺ regulatory T cells <i>via</i> inducible costimulator (ICOS), which was confirmed <i>in vivo</i>. Transfer of MPO/BAY dendritic cell-induced regulatory T cells <i>in vivo</i>, with or without anti-IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN <i>via</i> IL-10. 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.