Abstract
We previously reported the protection from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) by the adoptive transfer of genetically modified embryonic stem cell-derived dendritic cells (ES-DC) presenting MOG peptide in the context of MHC class II molecules and simultaneously expressing TRAIL (ES-DC-TRAIL/MOG). In the present study, we found the severity of EAE induced by another myelin autoantigen, myelin basic protein, was also decreased after treatment with ES-DC-TRAIL/MOG. This preventive effect diminished, if the function of CD4(+)CD25(+) regulatory T cells (Treg) was abrogated by the injection of anti-CD25 mAb into mice before treatment with ES-DC-TRAIL/MOG. The adoptive transfer of CD4(+)CD25(+) T cells from ES-DC-TRAIL/MOG-treated mice protected the recipient mice from MOG- or myelin basic protein-induced EAE. The number of Foxp3(+) cells increased in the spinal cords of mice treated with ES-DC-TRAIL/MOG. In vitro experiments showed that TRAIL expressed in genetically modified ES-DC and also in LPS-stimulated splenic macrophages had a capacity to augment the proliferation of CD4(+)CD25(+) T cells. These results suggest that the prevention of EAE by treatment with ES-DC-TRAIL/MOG is mediated, at least in part, by MOG-reactive CD4(+)CD25(+) Treg propagated by ES-DC-TRAIL/MOG. For the treatment of organ-specific autoimmune diseases, induction of Treg reactive to the organ-specific autoantigens by the transfer of DC-presenting Ags and simultaneously overexpressing TRAIL therefore appears to be a promising strategy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / immunology
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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / immunology
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Cell Movement
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Cell Proliferation
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Cells, Cultured
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Forkhead Transcription Factors / metabolism
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Genetic Engineering
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Interleukin-2 Receptor alpha Subunit / metabolism
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Lipopolysaccharides / pharmacology
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Mice
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Myelin Basic Protein / pharmacology
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Myelin Proteins
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Myelin-Associated Glycoprotein / genetics
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Myelin-Associated Glycoprotein / metabolism*
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Myelin-Associated Glycoprotein / therapeutic use
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Myelin-Oligodendrocyte Glycoprotein
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Spinal Cord / pathology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism*
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
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TNF-Related Apoptosis-Inducing Ligand / therapeutic use
Substances
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Antibodies, Monoclonal
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FOXP3 protein, human
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Forkhead Transcription Factors
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Interleukin-2 Receptor alpha Subunit
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Lipopolysaccharides
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MOG protein, human
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Mog protein, mouse
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Myelin Basic Protein
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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TNF-Related Apoptosis-Inducing Ligand