Tolerogenic IL-10-engineered dendritic cell-based therapy to restore antigen-specific tolerance in T cell mediated diseases
Laura Passeri, Grazia Andolfi, Virginia Bassi, Fabio Russo, Giorgia Giacomini, Cecilia Laudisa, Ilaria Marrocco, Luca Cesana, Marina Di Stefano, Lorella Fanti, Paola Sgaramella, Serena Vitale, Chiara Ziparo, Renata Auricchio, Graziano Barera, Giovanni Di Nardo, Riccardo Troncone, Carmen Gianfrani, Andrea Annoni, Laura Passerini, Silvia Gregori
Abstract
Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cell responses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficiently generate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding for immunodominant 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 subjects and celiac disease patients in vitro. In addition, DCIL−10/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 the induction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in pre-clinical disease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetes development. Collectively these data indicate that DCIL−10/Ag represent a platform to induce stable antigen-specific tolerance to control T-cell mediated diseases.