Tolerogenic dendritic cells modified by tacrolimus suppress CD4+ T-cell proliferation and inhibit collagen-induced arthritis in mice

Tolerogenic dendritic cells (tDCs) can be generated in vitro by a variety of methods, including genetic or pharmacological modification. DCs that were modified by the immunosuppressive drug tacrolimus were considered to be endowed with tolerogenic functions. DCs derived from human monocytes were ind...

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Veröffentlicht in:International immunopharmacology 2014-07, Vol.21 (1), p.247-254
Hauptverfasser: Ren, Yana, Yang, Yiming, Yang, Jie, Xie, Rufeng, Fan, Huahua
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Yang, Yiming
Yang, Jie
Xie, Rufeng
Fan, Huahua
description Tolerogenic dendritic cells (tDCs) can be generated in vitro by a variety of methods, including genetic or pharmacological modification. DCs that were modified by the immunosuppressive drug tacrolimus were considered to be endowed with tolerogenic functions. DCs derived from human monocytes were induced in vitro by GM-CSF/IL-4 with tacrolimus. The phenotype and production of cytokines in these DCs were analyzed. The functionality of tDCs modified by tacrolimus was subsequently determined via a CFSE proliferation assay. The severity of arthritis was monitored in CIA mice after treatment with tDCs modified by tacrolimus. tDCs that were modified by tacrolimus exhibited an immature phenotype. The expression of mRNA encoding IL-10 and TGF-β increased after 12h of tacrolimus stimulation, with the strongest responses being observed after 24h. The mRNA was further upregulated after tDCs were treated with LPS and IFN-γ. tDCs secreted more IL-10 and less TNF-α and had a reduced ability to activate allo-CD4+CD25− T cells. These cells suppressed mDC-induced-proliferation of CD4+CD25− T cells and produced less TNF-α and IFN-γ but increased the level of IL-10 than imDCs. Treatment of arthritic mice with tDCs modified by tacrolimus significantly inhibited the severity and progression of the disease. tDC treatment also altered the proportion of the Th1 and Th17 populations in the spleen. tDCs modified by tacrolimus suppressed CD4+ T cell proliferation and inhibited collagen-induced arthritis. These results suggest the potential use of tDCs as a therapeutic approach for autoimmune arthritis. •DCs modified by tacrolimus are tolerogenic DCs.•They were suppressive towards T cells proliferation by increasing IL-10.•They inhibited arthritis by altering the proportion of Th1 and Th17 populations.
doi_str_mv 10.1016/j.intimp.2014.05.004
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DCs that were modified by the immunosuppressive drug tacrolimus were considered to be endowed with tolerogenic functions. DCs derived from human monocytes were induced in vitro by GM-CSF/IL-4 with tacrolimus. The phenotype and production of cytokines in these DCs were analyzed. The functionality of tDCs modified by tacrolimus was subsequently determined via a CFSE proliferation assay. The severity of arthritis was monitored in CIA mice after treatment with tDCs modified by tacrolimus. tDCs that were modified by tacrolimus exhibited an immature phenotype. The expression of mRNA encoding IL-10 and TGF-β increased after 12h of tacrolimus stimulation, with the strongest responses being observed after 24h. The mRNA was further upregulated after tDCs were treated with LPS and IFN-γ. tDCs secreted more IL-10 and less TNF-α and had a reduced ability to activate allo-CD4+CD25− T cells. These cells suppressed mDC-induced-proliferation of CD4+CD25− T cells and produced less TNF-α and IFN-γ but increased the level of IL-10 than imDCs. Treatment of arthritic mice with tDCs modified by tacrolimus significantly inhibited the severity and progression of the disease. tDC treatment also altered the proportion of the Th1 and Th17 populations in the spleen. tDCs modified by tacrolimus suppressed CD4+ T cell proliferation and inhibited collagen-induced arthritis. These results suggest the potential use of tDCs as a therapeutic approach for autoimmune arthritis. •DCs modified by tacrolimus are tolerogenic DCs.•They were suppressive towards T cells proliferation by increasing IL-10.•They inhibited arthritis by altering the proportion of Th1 and Th17 populations.</description><identifier>ISSN: 1567-5769</identifier><identifier>EISSN: 1878-1705</identifier><identifier>DOI: 10.1016/j.intimp.2014.05.004</identifier><identifier>PMID: 24836681</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Arthritis, Experimental - immunology ; Arthritis, Experimental - therapy ; CD4-Positive T-Lymphocytes - immunology ; Cell Differentiation - drug effects ; Cell Proliferation ; Cell therapy ; Cells, Cultured ; Collagen-induced arthritis ; Cytokines - genetics ; Cytokines - metabolism ; Dendritic Cells - drug effects ; Dendritic Cells - immunology ; Dendritic Cells - transplantation ; Disease Progression ; Gene Expression Regulation - drug effects ; Humans ; Immune Tolerance ; Immunosuppression ; Immunotherapy - methods ; Male ; Mice ; Mice, Inbred DBA ; Tacrolimus ; Tacrolimus - pharmacology ; Tolerogenic dendritic cells ; Tolerogenic function</subject><ispartof>International immunopharmacology, 2014-07, Vol.21 (1), p.247-254</ispartof><rights>2014 Elsevier B.V.</rights><rights>Copyright © 2014 Elsevier B.V. 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subjects Animals
Arthritis, Experimental - immunology
Arthritis, Experimental - therapy
CD4-Positive T-Lymphocytes - immunology
Cell Differentiation - drug effects
Cell Proliferation
Cell therapy
Cells, Cultured
Collagen-induced arthritis
Cytokines - genetics
Cytokines - metabolism
Dendritic Cells - drug effects
Dendritic Cells - immunology
Dendritic Cells - transplantation
Disease Progression
Gene Expression Regulation - drug effects
Humans
Immune Tolerance
Immunosuppression
Immunotherapy - methods
Male
Mice
Mice, Inbred DBA
Tacrolimus
Tacrolimus - pharmacology
Tolerogenic dendritic cells
Tolerogenic function
title Tolerogenic dendritic cells modified by tacrolimus suppress CD4+ T-cell proliferation and inhibit collagen-induced arthritis in mice
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