title: Mitomycin C-treated dendritic cells inactivate autoreactive T cells: toward the development of a tolerogenic vaccine in autoimmune diseases.
abstract: Treatment of autoimmune diseases remains a challenge for immunological research. An ideal therapy should inhibit the immune reaction against the diseased organ and leave the rest of the immune response intact. Our previous studies showed that donor-derived dendritic cells (DCs) treated in vitro with mitomycin C (MMC) suppress rat heart allograft rejection if injected into recipients before transplantation. Here we analyze their efficacy in controlling autoimmunity. MMC-DCs loaded with myelin-basic-protein (MBP) inhibited specific T cells derived from multiple sclerosis patients in vitro. If coincubated with MMC-DCs, T cells were arrested in the G(0)/G(1) cell cycle phase. Microarray gene scan showed that MMC influences the expression of 116 genes in DCs, one main cluster comprising apoptotic and the second cluster immunosuppressive genes. Apparently, the combination of apoptosis with expression of tolerogenic molecules renders MMC-DCs suppressive. MBP-loaded MMC-DCs also inhibited mouse T cells in vitro and, in contrast to MBP-loaded naïve DCs, did not induce experimental autoimmune encephalitis. Most importantly, mice vaccinated with inhibitory DCs became resistant to the disease. Whereas this is not the first report on generation of suppressive DCs, it delineates a method using a clinically approved drug at nontoxic concentrations, which yields irreversibly changed DCs, effective across species in vitro and in vivo.
authors.affiliation: Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany. peter.terness@med.uni-heidelberg.de
authors.forename: Peter
authors.initials: P
authors.lastname: Terness
authors.forename: Thilo
authors.initials: T
authors.lastname: Oelert
authors.forename: Sandra
authors.initials: S
authors.lastname: Ehser
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Chuang
authors.forename: Imad
authors.initials: I
authors.lastname: Lahdou
authors.forename: Christian
authors.initials: C
authors.lastname: Kleist
authors.forename: Florian
authors.initials: F
authors.lastname: Velten
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Gerhard
authors.initials: G
authors.lastname: Opelz
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control; D016193:G1 Phase; D051379:Mice; D008822:Mice, Transgenic; D016685:Mitomycin / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014612:Vaccines / Q000276:immunology*
chemical_list: D014612:Vaccines; D016685:Mitomycin