Constitutive IL-1RA production by modified immune cells protects against IL-1–mediated inflammatory disorders
Mariasilvia Colantuoni, Raisa Jofra Hernández, Emanuela Pettinato, Luca Basso‐Ricci, Laura Magnani, Grazia Andolfi, Chiara Rigamonti, Annamaria Finardi, Valentina Romeo, Monica Soldi, Lucia Sergi Sergi, Martina Rocchi, Serena Scala, Hal M. Hoffman, Silvia Gregori, Anna Kajaste‐Rudnitski, Francesca Sanvito, Luca Muzio, Luigi Naldini, Alessandro Aiuti, Alessandra Mortellaro
Abstract
Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients' quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)-mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA-encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1-dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1-driven inflammation.