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Transplantation of Bone Marrow Transduced to Express Self-Antigen Establishes Deletional Tolerance and Permanently Remits Autoimmune Disease¹

James Chan^*, Ee Jun Ban^2,*, Keng Hao Chun^2,*, Shunhe Wang, B. Thomas Bäckström, Claude C. A. Bernard, Ban-Hock Toh^2,3,* and Frank Alderuccio^2,¶

^* Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Pathology, Chongqing Medical University, Chongqing, China; Malaghan Institute of Medical Research, Department of Pathology and Molecular Medicine, Wellington School of Medicine, Wellington South, New Zealand; and Monash Immunology and Stem Cell Laboratories and ^¶ Department of Immunology, Monash University, Melbourne, Victoria, Australia

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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by program grants from the National Health and Medical Research Council of Australia, Cure MS (Australia), the Baker Foundation, and the National Multiple Sclerosis Society of New York.

² E.J.B., K.H.C., B-H.T., and F.A. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Ban-Hock Toh, Centre for Inflammatory Diseases, Department of Medicine, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail address: Ban-Hock.Toh{at}med.monash.edu.au

⁴ Abbreviations used in this paper: BMT, bone marrow transplantation; BM, bone marrow; DC, dendritic cell; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; Treg, regulatory T cell; Tg, transgenic; ProII, proinsulin II; pMOG, retrovirus encoding MOG; pProII, retrovirus encoding ProII; eGFP, enhanced GFP; RT, room temperature; nBM, normal bone marrow.