Gene therapy for immunological tolerance: using 'transgenic' B cells to treat inhibitor formation.
B cells have been shown to function as tolerogenic antigen presenting cells (APCs) both in vivo and in vitro. We have taken advantage of this property, as well as the ability of IgG carriers to be potent 'schleppers' for tolerogenic entities, to develop a gene therapy approach to induce unresponsiveness in a number of systems, including the elimination of haemophilia inhibitors. Thus, peptide-IgG constructs have been engineered into retroviral vectors to create 'transgenic' B cells for tolerance applications. In this paper, we discuss our gene therapy approach mediated by B cells (as well as bone marrow cells) for tolerance acquisition in various mouse models for autoimmune disease and haemophilia A. The mechanisms that are the underpinning of this effort and role of regulatory T cells are discussed herein. Our results indicate that gene therapy strategies can successfully reduce the incidence and or onset of autoimmune diseases and prevent/reverse inhibitor formation in haemophilia A mice. Based on recent success with a model for tolerance with human T cell clones in vitro, plans for future application in patients are discussed.
Department of Surgery, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA. davscott@som.umaryland.edu
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D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control* / Q000628:therapy*; D001402:B-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006467:Hemophilia A / Q000517:prevention & control* / Q000628:therapy*; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics* / Q000502:physiology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D009103:Multiple Sclerosis / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes; D014161:Transduction, Genetic; D014605:Uveitis / Q000276:immunology
D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D010455:Peptides