title: Specific immunotherapy of experimental myasthenia gravis in vitro: the "guided missile" strategy.
abstract: We describe a strategy for specific immunotherapy of myasthenia gravis (MG) based on genetic engineering of antigen presenting cells (APCs) to present the autoantigen acetylcholine receptor (AChR) and express the "warhead" Fas ligand (FasL). For transduction of APCs we prepared recombinant attenuated vaccinia virus vectors carrying the following three gene constructs: (i) AChR fused to LAMP1 to present AChR and target AChR-specific T cells; (ii) FasL to eliminate the targeted T cells; and (iii) truncated FADD to protect APCs from self-destruction by FasL. The engineered APCs effectively expressed the genes of interest and killed AChR-specific T cells in culture by the Fas/FasL pathway. T cells specific for an unrelated antigen were spared. Our in vitro demonstration that engineered APCs target and kill antigen-specific T cells represents a promising novel strategy for specific immunotherapy of MG and other autoimmune diseases.
authors.affiliation: Neuromuscular Research Laboratory, Johns Hopkins School of Medicine, Baltimore, Maryland, 21287-7519, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Wu
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.forename: A
authors.initials: A
authors.lastname: Miagkov
authors.forename: R N
authors.initials: RN
authors.lastname: Adams
authors.forename: D B
authors.initials: DB
authors.lastname: Drachman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors; D007167:Immunotherapy; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus; D019014:fas Receptor / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D001324:Autoantigens; D002352:Carrier Proteins; C505534:Fadd protein, mouse; C505535:Fadd protein, rat; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; D019014:fas Receptor