Nonmyeloablative Conditioning Generates Autoantigen‐Encoding Bone Marrow That Prevents and Cures an Experimental Autoimmune Disease

• Published in: American journal of transplantation Vol. 12; no. 8; pp. 2062 - 2071
• Main Authors: Nasa, Z., Chung, J.‐Y., Chan, J., Toh, B.‐H., Alderuccio, F.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.08.2012; Wiley
• Subjects: Allografts; Animal models; Animals; Autoantigens; Autoantigens - immunology; Autografts; Autoimmune diseases; Autoimmune Diseases - surgery; Base Sequence; Biological and medical sciences; Bone marrow; Bone Marrow - immunology; Busulfan - analogs & derivatives; Busulfan - pharmacology; Chimeras; Chimerism; Disease resistance; DNA Primers; Enzyme-Linked Immunosorbent Assay; Experimental allergic encephalomyelitis; Experimental autoimmune encephalomyelitis; Female; Flow Cytometry; gene therapy; hematopoietic stem cell transfer; Humans; Immune response; Immunological tolerance; Medical sciences; Mice; Mice, Inbred C57BL; multiple sclerosis; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; nonmyeloablative; Oligodendrocyte-myelin glycoprotein; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Radiation; Reverse Transcriptase Polymerase Chain Reaction; stem cell transplantation; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Transplantation Conditioning; treosulfan; Autoimmunity; Immunopathology; Animal model; Nervous system diseases; Multiple sclerosis; nonmyeloablative; Cure; Stem cell; Hematopoietic cell; Experimental autoimmune encephalomyelitis; Autoimmune disease; Non myeloablative treatment; Experimental allergic encephalomyelitis; Inflammatory disease; Prevention; Experimental disease; Autoantigen; Treatment; hematopoietic stem cell transfer; Central nervous system disease; Bone marrow; Transfer; Gene therapy
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2012.04068.x

Autoimmune diseases result from chronic targeted immune responses that lead to tissue pathology and disease. The potential of autologous hematopoietic stem cells transplantation as a treatment for autoimmunity is currently being trialled but disease relapse is an issue. We have previously shown in a mouse model of experimental autoimmune encephalomyelitis (EAE) that the transplantation of bone marrow (BM) transduced to encode the autoantigen myelin oligodendrocyte glycoprotein (MOG) can prevent disease induction. However these studies were performed using lethal irradiation to generate BM chimeras and a critical factor for translation to humans would be the ability to utilize low toxic preconditioning regimes. In this study, treosulfan was used as a nonmyeloablative agent to generate BM chimeras encoding MOG and assessed in models of EAE induction and reversal. We find that treosulfan conditioning can promote a low degree of chimerism that is sufficient to promote antigen specific tolerance and protect mice from EAE. When incorporated into a curative protocol for treating mice with established EAE, nonmyeloablative conditioning and low chimerism was equally efficient in maintaining disease resistance. These studies further underpin the potential and feasibility of utilizing a gene therapy approach to treat autoimmune disease. The authors use a gene‐therapy approach to demonstrate that low‐level chimerism generated with nonmyeloablative conditioning is sufficient to promote tolerance and treat mice with experimental autoimmune encephalomyelitis.