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Bone marrow transplantation combined with gene therapy to induce antigen-specific tolerance and ameliorate EAE.

Abstract
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.
AuthorsBiying Xu, Peter Haviernik, Lawrence A Wolfraim, Kevin D Bunting, David W Scott
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 13 Issue 1 Pg. 42-8 (Jan 2006) ISSN: 1525-0016 [Print] United States
PMID16219491 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • CD4 Antigens
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • Receptors, Interleukin-2
  • myelin proteolipid protein (139-151)
  • L-Selectin
  • Green Fluorescent Proteins
Topics
  • Animals
  • Bone Marrow Cells (metabolism)
  • Bone Marrow Transplantation
  • CD4 Antigens (immunology)
  • Cell Proliferation
  • Combined Modality Therapy
  • Encephalomyelitis, Autoimmune, Experimental (immunology, radiotherapy, therapy)
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Green Fluorescent Proteins (genetics)
  • Humans
  • Immune Tolerance
  • Immunization
  • L-Selectin (immunology)
  • Mice
  • Myelin Proteolipid Protein (genetics, immunology, metabolism)
  • Peptide Fragments (genetics, immunology, metabolism)
  • Receptors, Interleukin-2 (immunology)
  • T-Lymphocytes (immunology, pathology)

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