Tolerogenic IL-10-engineered dendritic cell-based therapy to restore antigen-specific tolerance in T cell mediated diseases

Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cellresponses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficientlygenerate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding forimmunodominant antigen-derived peptides and IL-10. These transduced dendritic cells (designated DCIL? 10/Ag)secrete IL-10 and efficiently downregulate antigen-specific CD4+ and CD8+ T cell responses from healthy subjectsand celiac disease patients in vitro. In addition, DC-IL10/Ag induce antigen-specific CD49b+LAG-3+ T cells,which display the T regulatory type 1 (Tr1) cell gene signature. Administration of DCIL? 10/Ag resulted in theinduction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in preclinicaldisease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetesdevelopment. Collectively these data indicate that DC-IL10/Ag represent a platform to induce stable antigen specifictolerance to control T-cell mediated diseases.