Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand.
Experimental autoimmune encephalomyelitis (EAE) is caused by activation of myelin Ag-reactive CD4+ T cells. In the current study, we tested a strategy to prevent EAE by pretreatment of mice with genetically modified dendritic cells (DC) presenting myelin oligodendrocyte glycoprotein (MOG) peptide in the context of MHC class II molecules and simultaneously expressing TRAIL or Programmed Death-1 ligand (PD-L1). For genetic modification of DC, we used a recently established method to generate DC from mouse embryonic stem cells (ES cells) in vitro (ES-DC). ES cells were sequentially transfected with an expression vector for TRAIL or PD-L1 and an MHC class II-associated invariant chain-based MOG epitope-presenting vector. Subsequently, double-transfectant ES cell clones were induced to differentiate to ES-DC, which expressed the products of introduced genes. Treatment of mice with either of the double-transfectant ES-DC significantly reduced T cell response to MOG, cell infiltration into spinal cord, and the severity of MOG peptide-induced EAE. In contrast, treatment with ES-DC expressing MOG alone, irrelevant Ag (OVA) plus TRAIL, or OVA plus PD-L1, or coinjection with ES-DC expressing MOG plus ES-DC-expressing TRAIL or PD-L1 had no effect in reducing the disease severity. In contrast, immune response to irrelevant exogenous Ag (keyhole limpet hemocyanin) was not impaired by treatment with any of the genetically modified ES-DC. The double-transfectant ES-DC presenting Ag and simultaneously expressing immune-suppressive molecules may well prove to be an effective therapy for autoimmune diseases without inhibition of the immune response to irrelevant Ag.
Hirata
Shinya
S
Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Senju
Satoru
S
Matsuyoshi
Hidetake
H
Fukuma
Daiki
D
Uemura
Yasushi
Y
Nishimura
Yasuharu
Y
D019264:Adoptive Transfer / Q000379:methods; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage* / Q000235:genetics; D015202:Protein Engineering; D033581:Stem Cell Transplantation / Q000379:methods*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D019076:Transgenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010455:Peptides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55)