Tolerogenic cells: biology and approaches for their application to prevent unwanted immune responses in protein/gene replacement therapies

Enzyme Replacement Therapy (ERT) is the main treatment for several Lysosomal Storage Disorders (LSDs). Nevertheless, immune responses directed towards recombinant enzymes induce severe adverse inflammatory events in some patients and may limit the efficacy of the therapy itself. Active induction of immune tolerance is an encouraging strategy to limit unwanted immune responses and foster the efficacy of protein replacement therapy. Cell therapy based on the infusion of tolerogenic dendritic cell (tolDC) represents a promising experimental approach aimed at controlling adverse immune responses and promoting tolerance. This treatment has been applied in clinical trials with variable outcomes. In recent years, our group has developed protocols based on the administration of tolDC generated in the presence of IL-10 or genetically modified and demonstrated their efficacy in modulating antigen-specific T cell responses in vitro and in vivo. In the hypothesis that tolDC-based cell therapy could be an innovative strategy to prevent and/or modulate the adverse responses induced by ERT in LSD patients, the aim of this project is to develop engineered tolDCs that can efficiently foster enzyme-specific tolerance in LSDs and that could be used in the future as specific adjuvant immunotherapy for ERT-treated patients. Through in vivo and in vitro studies, we aim to: 1. characterize the mechanisms that promote the differentiation of tolDC with the aim of finding new tools for the generation of efficient tolDCs, 2. evaluate the immune responses to the missing enzyme in patients with LSD treated with ERT (e.g., Mucopolysaccharidosis and Pompe disease), 3. to develop a new cell therapy based on the use of tolDC to modulate the unwanted immune responses induced by ERT in LSD patients. Using state-of-the-art molecular studies, immunological characterization of LSD patients’ immune response, and technology development of tolDC, we expect to identify new and efficient antigen-specific tolerogenic strategies to evade the adverse immune responses induced by ERT. Results will open the development of a cell therapy that could be used as an adjuvant treatment to efficiently prevent adverse immune responses in patients undergoing enzyme / protein replacement therapy and after gene therapy.