Tolerogenic Dendritic Cells Engineered with a Lentiviral Vector Encoding for IL-10 and Antigen Control T Cell Responses to Pathogenic Antigens

Wednesday, June 22, 2022

5:00 PM – 5:15 PM PT

Location: Salons 3/4

Authors: Laura Passerini, n/a (Presenting Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute; Laura Passeri, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR.Tiget), San Raffaele Scientific Institute; Grazia Andolfi, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute; Andrea Annoni, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute; Luca Cesana, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute; Giorgia Giacomini, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute; Virginia Bassi, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute; Paola Sgaramella, n/a (Co-Author) - Department of Paediatrics, San Raffaele Scientific Institute; Marina Di Stefano, n/a (Co-Author) - Department of Paediatrics, San Raffaele Scientific Institute; Graziano Barera, n/a (Co-Author) - Department of Paediatrics, San Raffaele Scientific Institute; Lorella Fanti, n/a (Co-Author) - Gastroenterology and Gastrointestinal Endoscopy Unit, San Raffaele Scientific Institute; Carmen Gianfrani, n/a (Co-Author) - Institute of Biochemistry and Cell Biology, CNR; Serena Vitale, n/a (Co-Author) - Institute of Biochemistry and Cell Biology, CNR; Riccardo Troncone, n/a (Co-Author) - European Laboratory of the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II; Renata Auricchio, n/a (Co-Author) - European Laboratory of the Investigation of Food Induced Diseases, Department of Translational Medical Science, Section of Pediatrics, and ELFID, University Federico II; Giovanni Di Nardo, n/a (Co-Author) - NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome and Sant'Andrea University Hospital; Chiara Ziparo, n/a (Co-Author) - NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome and Sant'Andrea University Hospital; Silvia Gregori, n/a (Co-Author) - San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute

Presenting Author(s)

Laura Passerini

Reasearch Associate
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), San Raffaele Scientific Institute
Milan, Lombardia, Italy

Chair(s)

Marianna Rowlands, PhD

Associate Director
Novartis Institutes for Biomedical Research
Cambridge, Massachusetts, United States

Tolerogenic dendritic cells (tolDC) play a crucial role in promoting tolerance and represent the cells of choice to fulfill the goal of restoring antigen(Ag)-specific tolerance in autoimmunity. Effective DC-based therapy should dampen autoreactive T cell responses, inducing pathogenic T cell exhaustion, and restore long-term tolerancevia Ag-specific regulatory T cell (Treg) induction. Here we show that in vitro differentiation of DC viatransduction with bidirectional lentiviral vectors encoding for the Ag of interest (Ovalbumin or Matrix Protein 1 as model Ags, or insulin-/gliadin-derived peptides, as disease-specific Ags) in combination with IL-10 from both human and murine precursors allows efficient generation of tolDC (DC^IL-10/Ag), which secrete high amounts of IL-10 in the absence of pro-inflammatory cytokines. DC^IL-10/Agefficiently modulated in vitro activation and proliferation of Ag-specific CD4⁺ and CD8⁺ T cells. Repetitive administration of DC^IL-10/Ag in vivo promoted OVA-specific CD4⁺ type 1 regulatory T (Tr1) cells, CD8⁺ T cells with an exhausted phenotype (CD44⁺PD-1⁺LAG-3⁺TIM-3⁺) and prevented T1D development in two distinct murine models of disease. Human DC^IL-10/Agpromoted the in vitro induction of Ag-specific CD49b⁺LAG-3⁺ T cells, which displayed the Tr1 cell gene signature and modulated gliadin-specific CD4⁺ T cell responses of Celiac Disease patients.We developed engineered tolDC that effectively modulate pathogenic CD4⁺ and CD8⁺ T cell responses in vitro and in vivo, by promoting Ag-specific Tr1 cells and CD8⁺ T cells with an exhausted phenotype. These results lead to the definition of an innovative approach based on the use of autologous DC to restore tolerance in T cell-mediated diseases.