Transcriptional targeting of DCs with lentiviral vectors induces antigen-specific tolerance in a mouse model of multiple sclerosis

The aim of this work was to induce permanent tolerance toward self-antigens involved in autoimmune diseases, such as multiple sclerosis (MS). We hypothesized that the stable auto-antigen presentation by dendritic cells (DCs) would tolerize auto-reactive T cells and, therefore, prevent disease development in a mouse model of experimental autoimmune encephalomyelitis (EAE), which closely resembles MS. Specifically, our strategy included the ex vivo modification of hematopoietic stem cells (HSCs) with self-inactivating (SIN) lentivirus vectors that transcriptionally target the expression of myelin antigens to DCs. As SIN lentivirus vectors support the genomic integration of transgene sequences in HSC, the transduced and transplanted HSC may provide a constant supply of antigen expressing steady-state DCs. Here, we demonstrate that targeting myelin oligodendrocyte glycoprotein (MOG) expression to DCs indeed resulted in complete and stable protection from EAE. No histological signs of EAE, such as demyelination, axonal damage, or infiltration of leukocytes in brain, spinal cord and optical nerve, were observed in tolerized mice. Tolerance induction was concomitant with the efficient deletion of MOG-specific T cells and the generation of Foxp3(+) regulatory T cells and, most importantly, directed toward a specific self-antigen while T-cell reactivity to unrelated foreign antigens was fully preserved

Targeting dendritic cells to treat multiple sclerosis

Multiple sclerosis (MS) is considered to be a predominantly T-cell-mediated disease, and emerging evidence indicates that dendritic cells have a critical role in the initiation and progression of this debilitating condition. Dendritic cells are specialized antigen-presenting cells that can prime naive T cells and modulate adaptive immune responses. Their powerful biological functions indicate that these cells can be exploited by immunotherapeutic approaches. Therapies that inhibit the immunogenic actions of dendritic cells through the blockade of proinflammatory cytokine production and T cell co-stimulatory pathways are currently being pursued. Furthermore, novel strategies that can regulate dendritic cell development and differentiation and harness the tolerogenic capacity of these cells are also being developed. Here, we evaluate the prospects of these future therapeutic strategies, which focus on dendritic cells and dendritic cell-related targets to treat MS