Bone marrow transplantation combined with gene therapy to induce antigen-specific tolerance and ameliorate EAE.
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.
Xu
Biying
B
Department of Surgery, University of Maryland, Baltimore, MD 21201, USA.
Haviernik
Peter
P
Wolfraim
Lawrence A
LA
Bunting
Kevin D
KD
Scott
David W
DW
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000276:immunology; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000532:radiotherapy / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D019041:L-Selectin / Q000276:immunology; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D015704:CD4 Antigens; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; C435023:myelin proteolipid protein (139-151); D019041:L-Selectin; D049452:Green Fluorescent Proteins