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Thymic gene transfer of myelin oligodendrocyte glycoprotein ameliorates the onset but not the progression of autoimmune demyelination

Siatskas, Christopher; Seach, Natalie; Sun, Guizhi; Emerson-Webber, Ashley; Silvain, Aude; Toh, Ban-Hock; Alderuccio, Frank; Bäckström, B Thomas LU ; Boyd, Richard L and Bernard, Claude C (2012) In Molecular Therapy 20(7). p.59-1349
Abstract

Tolerance induction, and thus prevention of autoimmunity, is linked with the amount of self-antigen presented on thymic stroma. We describe that intrathymic (i.t.) delivery of the autoantigen, myelin oligodendrocyte glycoprotein (MOG), via a lentiviral vector (LV), led to tolerance induction and prevented mice from developing fulminant experimental autoimmune encephalomyelitis (EAE). This protective effect was associated with the long-term expression of antigen in transduced stromal cells, which resulted in the negative selection of MOG-specific T cells and the generation of regulatory T cells (Tregs). These selection events were effective at decreasing T-cell proliferative responses and reduced Th1 and Th17 cytokines. In vivo, this... (More)

Tolerance induction, and thus prevention of autoimmunity, is linked with the amount of self-antigen presented on thymic stroma. We describe that intrathymic (i.t.) delivery of the autoantigen, myelin oligodendrocyte glycoprotein (MOG), via a lentiviral vector (LV), led to tolerance induction and prevented mice from developing fulminant experimental autoimmune encephalomyelitis (EAE). This protective effect was associated with the long-term expression of antigen in transduced stromal cells, which resulted in the negative selection of MOG-specific T cells and the generation of regulatory T cells (Tregs). These selection events were effective at decreasing T-cell proliferative responses and reduced Th1 and Th17 cytokines. In vivo, this translated to a reduction in inflammation and demyelination with minimal, or no axonal loss in the spinal cords of treated animals. Significantly intrathymic delivery of MOG to mice during the priming phase of the disease failed to suppress clinical symptoms despite mice being previously treated with a clearing anti-CD4 antibody. These results indicate that targeting autoantigens to the thymic stroma might offer an alternative means to induce the de novo production of tolerant, antigen-specific T cells; however, methods that control the number and or the activation of residual autoreactive cells in the periphery are required to successfully treat autoimmune neuroinflammation.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Disease Progression, Encephalomyelitis, Autoimmune, Experimental/genetics, Female, Genetic Vectors, Immune Tolerance, Lentivirus/genetics, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myelin-Oligodendrocyte Glycoprotein/biosynthesis, Random Allocation, Th1 Cells/immunology, Th17 Cells/immunology, Thymus Gland/immunology, Transduction, Genetic
in
Molecular Therapy
volume
20
issue
7
pages
59 - 1349
publisher
Nature Publishing Group
external identifiers
  • scopus:84863445336
ISSN
1525-0024
DOI
10.1038/mt.2012.15
language
English
LU publication?
no
id
0faec6df-3b26-40a7-82be-283bfbeccf67
date added to LUP
2018-10-08 22:11:57
date last changed
2019-02-20 11:30:02
@article{0faec6df-3b26-40a7-82be-283bfbeccf67,
  abstract     = {<p>Tolerance induction, and thus prevention of autoimmunity, is linked with the amount of self-antigen presented on thymic stroma. We describe that intrathymic (i.t.) delivery of the autoantigen, myelin oligodendrocyte glycoprotein (MOG), via a lentiviral vector (LV), led to tolerance induction and prevented mice from developing fulminant experimental autoimmune encephalomyelitis (EAE). This protective effect was associated with the long-term expression of antigen in transduced stromal cells, which resulted in the negative selection of MOG-specific T cells and the generation of regulatory T cells (Tregs). These selection events were effective at decreasing T-cell proliferative responses and reduced Th1 and Th17 cytokines. In vivo, this translated to a reduction in inflammation and demyelination with minimal, or no axonal loss in the spinal cords of treated animals. Significantly intrathymic delivery of MOG to mice during the priming phase of the disease failed to suppress clinical symptoms despite mice being previously treated with a clearing anti-CD4 antibody. These results indicate that targeting autoantigens to the thymic stroma might offer an alternative means to induce the de novo production of tolerant, antigen-specific T cells; however, methods that control the number and or the activation of residual autoreactive cells in the periphery are required to successfully treat autoimmune neuroinflammation.</p>},
  author       = {Siatskas, Christopher and Seach, Natalie and Sun, Guizhi and Emerson-Webber, Ashley and Silvain, Aude and Toh, Ban-Hock and Alderuccio, Frank and Bäckström, B Thomas and Boyd, Richard L and Bernard, Claude C},
  issn         = {1525-0024},
  keyword      = {Animals,Disease Progression,Encephalomyelitis, Autoimmune, Experimental/genetics,Female,Genetic Vectors,Immune Tolerance,Lentivirus/genetics,Lymphocyte Activation,Mice,Mice, Inbred C57BL,Mice, Transgenic,Myelin-Oligodendrocyte Glycoprotein/biosynthesis,Random Allocation,Th1 Cells/immunology,Th17 Cells/immunology,Thymus Gland/immunology,Transduction, Genetic},
  language     = {eng},
  number       = {7},
  pages        = {59--1349},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Thymic gene transfer of myelin oligodendrocyte glycoprotein ameliorates the onset but not the progression of autoimmune demyelination},
  url          = {http://dx.doi.org/10.1038/mt.2012.15},
  volume       = {20},
  year         = {2012},
}