title: Transplantation of bone marrow transduced to express self-antigen establishes deletional tolerance and permanently remits autoimmune disease.
abstract: Autoimmune diseases are incurable. We have hypothesized that these diseases can be cured by the transplantation of bone marrow (BM) stem cells that have been genetically engineered to express self-Ag. Here we have tested this hypothesis in experimental autoimmune encephalomyelitis (EAE) induced by the self-Ag myelin oligodendrocyte glycoprotein (MOG). We show that, in mice, transplantation of BM genetically modified to express MOG prevented the induction and progression of EAE, and combined with antecedent corticosteroid treatment, induced long-term remission of established disease. Mice remained resistant to EAE development upon subsequent rechallenge with MOG. Transfer of BM from these mice rendered recipients resistant to EAE. Splenocytes from these mice failed to proliferate or produce IL-17, IFN-gamma, and GM-CSF in response to MOG(35-55) peptide stimulation and they failed to produce MOG autoantibody. Mechanistically, we demonstrated in vivo reduction in development of CD4(+) MOG(35-55)-specific thymocytes, indicative of clonal deletion with no evidence for selection of Ag-specific regulatory T cells. These findings validate our hypothesis that transplantation of genetically modified BM expressing disease-causative self-Ag provides a curative approach by clonal deletion of disease-causative self-reactive T cells.
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Chan
authors.forename: Ee Jun
authors.initials: EJ
authors.lastname: Ban
authors.forename: Keng Hao
authors.initials: KH
authors.lastname: Chun
authors.forename: Shunhe
authors.initials: S
authors.lastname: Wang
authors.forename: B Thomas
authors.initials: BT
authors.lastname: Bäckström
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
authors.forename: Ban-Hock
authors.initials: BH
authors.lastname: Toh
authors.forename: Frank
authors.initials: F
authors.lastname: Alderuccio
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D016026:Bone Marrow Transplantation; D017637:Clonal Deletion / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D000305:Adrenal Cortex Hormones; D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)