Abstract
As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNγ production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the IFNγ and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.
Original language | English (US) |
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Pages (from-to) | 719-731 |
Number of pages | 13 |
Journal | Immunity |
Volume | 21 |
Issue number | 5 |
DOIs | |
State | Published - Nov 2004 |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases