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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Christopher Siatskas
  • Natalie Seach
  • Guizhi Sun
  • Ashley Emerson-Webber
  • Aude Silvain
  • Ban-Hock Toh
  • Frank Alderuccio
  • B Thomas Bäckström
  • Richard L Boyd
  • Claude C Bernard
External organisations
  • Monash University
  • Novo Nordisk A/S
Research areas and keywords

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
Original languageEnglish
Pages (from-to)1349-59
JournalMolecular Therapy
Volume20
Issue number7
Publication statusPublished - 2012 Jul
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes