Lentiviral-mediated transcriptional targeting of dendritic cells for induction of T cell tolerance in vivo.
Dendritic cells (DCs) are important APCs able to induce both tolerance and immunity. Therefore, DCs are attractive targets for immune intervention. However, the ex vivo generation and manipulation of DCs at sufficient numbers and without changing their original phenotypic and functional characteristics are major obstacles. To manipulate DCs in vivo, we developed a novel DC-specific self-inactivating lentiviral vector system using the 5' untranslated region from the DC-STAMP gene as a putative promoter region. We show that a gene therapy approach with these DC-STAMP-lentiviral vectors yields long-term and cell-selective transgene expression in vivo. Furthermore, transcriptionally targeted DCs induced functional, Ag-specific CD4 and CD8 T cell tolerance in vivo, which could not be broken by viral immunization. Tolerized CTL were unable to induce autoimmune diabetes in a murine autoimmune model system. Therefore, delivering transgenes specifically to DCs by using viral vectors might be a promising tool in gene therapy.
Dresch
Christiane
C
Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany.
Edelmann
Stephanie L
SL
Marconi
Peggy
P
Brocker
Thomas
T
D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007328:Insulin / Q000008:administration & dosage / Q000235:genetics; D016086:Lentivirus / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000235:genetics; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic / Q000276:immunology*; D016662:Virus Integration / Q000235:genetics / Q000276:immunology
C499636:DC-STAMP protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010047:Ovalbumin