Viral vector mediated tolerance induction in experimental autoimmune encephalomyelitis by dendritic cell targeted expression of a self-antigen (115.2)

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune disease characterized by the presence of self-reactive T cells that target myelin components. Immunization of susceptible animals with myelin antigens induces experimental autoimmune encephalomyelitis (EAE), an animal model for MS. The aim of this project was to induce permanent, antigen-specific tolerance in EAE/MS and to address the mechanisms that would contribute to tolerance. The strategy includes the ex vivo modification of autologous hematopoietic stem cells (HSC) with lentiviral vectors that express myelin oligodendrocyte glycoprotein (MOG) under the control of a dendritic cell (DC) specific promoter. After re-infusion, the modified HSC will give rise to antigen expressing DCs. We demonstrated the effectiveness of this strategy for inducing MOG-specific tolerance in EAE, as 100% of the mice that received BM cells transduced with MOG-lentivector were protected. In addition, we show depletion of MOG specific T cells and generation of Foxp3+ regulatory T cells in chimeras that received HSC transduced with MOG-lentivector. As apposed to the protected animals, the diseased control mice showed high levels of IL-1, INF-γ and IL-17. The strategy presented here is particularly promising for clinical applications and important for addressing fundamental questions in immunity and tolerance.