Targeting MOG expression to dendritic cells delays onset of experimental autoimmune disease.
Haematopoietic stem cell (HSC) transfer coupled with gene therapy is a powerful approach to treating fatal diseases such as X-linked severe combined immunodeficiency. This ability to isolate and genetically manipulate HSCs also offers a strategy for inducing immune tolerance through ectopic expression of autoantigens. We have previously shown that retroviral transduction of bone marrow (BM) with vectors encoding the autoantigen, myelin oligodendrocyte glycoprotein (MOG), can prevent the induction of experimental autoimmune encephalomyelitis (EAE). However, ubiquitous cellular expression of autoantigen driven by retroviral promoters may not be the best approach for clinical translation and a targeted expression approach may be more acceptable. As BM-derived dendritic cells (DCs) play a major role in tolerance induction, we asked whether targeted expression of MOG, a target autoantigen in EAE, to DCs can promote tolerance induction and influence the development of EAE. Self-inactivating retroviral vectors incorporating the mouse CD11c promoter were generated and used to transduce mouse BM cells. Transplantation of gene-modified cells into irradiated recipients resulted in the generation of chimeric mice with transgene expression limited to DCs. Notably, chimeric mice transplanted with MOG-expressing BM cells manifest a significant delay in the development of EAE suggesting that targeted antigen expression to tolerogenic cell types may be a feasible approach to inducing antigen-specific tolerance.
Ko
Hyun-Ja
HJ
Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Chung
Jie-Yu
JY
Nasa
Zeyad
Z
Chan
James
J
Siatskas
Christopher
C
Toh
Ban-Hock
BH
Alderuccio
Frank
F
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology; D039521:CD11c Antigen / Q000235:genetics; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics* / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism
D039521:CD11c Antigen; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein