Bone Marrow Transplantation Combined with Gene Therapy to Induce Antigen-specific Tolerance and Ameliorate EAE

• Published in: Molecular therapy Vol. 13; no. 1; pp. 42 - 48
• Main Authors: Xu, Biying, Haviernik, Peter, Wolfraim, Lawrence A, Bunting, Kevin D, Scott, David W
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.01.2006
• Subjects: Animals; Antigens; Autoimmune diseases; Bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; CD4 Antigens - immunology; Cell growth; Cell Proliferation; Combined Modality Therapy; Diabetes; Disease; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - radiotherapy; Encephalomyelitis, Autoimmune, Experimental - therapy; Female; Gene therapy; Genetic Therapy; Genetic Vectors; Glycoproteins; Green Fluorescent Proteins - genetics; Humans; Immune system; Immune Tolerance; Immunization; L-Selectin - immunology; Lymphocytes; Mice; Multiple sclerosis; Myelin Proteolipid Protein - genetics; Myelin Proteolipid Protein - immunology; Myelin Proteolipid Protein - metabolism; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide Fragments - metabolism; Peptides; Proteins; Receptors, Interleukin-2 - immunology; Spleen; Stem cell transplantation; T-Lymphocytes - immunology; T-Lymphocytes - pathology; United States > US
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2005.09.002

Hematopoietic stem cell (HSC) transplantation is a potential therapy that can offer multiple sclerosis patients a radical, potentially curative treatment. Using experimental autoimmune encephalomyelitis (EAE) as a model, we previously reported that retrovirally transduced B cells expressing myelin basic protein (MBP), MBP Ac1-11, or myelin oligodendrocyte glycoprotein p35-55 induced tolerance and reduced symptoms. Here, we extend our tolerance approach using bone marrow (BM) cells expressing full-length phospholipid protein (PLP) in a model for relapsing, remitting EAE. Using GFP expression as a marker, we found that up to 50% of cells were positive for transgene expression in peripheral blood after 900 rad irradiation and transduced BM transplantation, and expression was stable in hematopoietic lineages for over 10 weeks. Upon challenge, T cell proliferation in response to PLP p139-151 was reduced and EAE was completely abolished in a pretreatment protocol. In addition, protection from EAE could be achieved with PLP-transduced BM cells given on day 12 after immunization, a potential therapeutic protocol. Finally, the protective effect of PLP-expressing BM could also be observed using a nonmyeloablative protocol, albeit with lower efficacy. Our results suggest that HSC may be useful to achieve long-lasting tolerance to protect mice from EAE and possibly to promote CNS repair in ongoing EAE.