Tu226 - Constitutive IL-1RA Production by Modified Immune Cells Protects Against Tissue and Systemic il-1-mediated Inflammatory Disorders

Raisa Jofra Hernandez – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Emanuela Pettinato – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Luca Basso-Ricci – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; laura Magnani – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Grazia Andolfi – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Chiara Rigamonti – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy 2 Vita-Salute San Raffaele University, Milan, Italy; Annamaria Finardi – 3 Neuroimmunology Unit, INSpe, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Valentina Romeo – 3 Neuroimmunology Unit, INSpe, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Monica Soldi – 4 Processing Developmental Laboratory, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Lucia Sergi sergi – 4 Processing Developmental Laboratory, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Martina Rocchi – 5 GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Serena Scala – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Hal M. Hoffman – 6 Department of Pediatrics, University of California at San Diego, La Jolla, California 92093, USA.; Silvia Gregori – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Anna Kajaste-Rudnitski – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy 2 Vita-Salute San Raffaele University, Milan, Italy; Francesca Sanvito – 5 GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy 7 Pathology Unit, Department of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; luca Muzio – 2 Vita-Salute San Raffaele University, Milan, Italy 3 Neuroimmunology Unit, INSpe, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Luigi Naldini – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy 2 Vita-Salute San Raffaele University, Milan, Italy; Alessandro Aiuti – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy 2 Vita-Salute San Raffaele University, Milan, Italy 8 Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Alessandra Mortellaro – 1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy

Abstract Text: IL-1 is a proinflammatory cytokine with multiple functions. While it is important for fighting infections and promoting healing, overproduction of IL-1 leads to severe inflammatory conditions. Anti-IL-1 blockade with anakinra, a recombinant form of the naturally occurring human IL-1-receptor antagonist (IL-1RA), is the standard of care for patients with autoinflammatory disorders. However, anakinra has several potential drawbacks, like a short half-life, poor tissue penetration, and side effects. To circumvent these limitations, we empowered immune cells with a stable IL-1RA production by adoptively transferring in mice hematopoietic stem-progenitor cells (HSPCs) transduced with a lentiviral vector encoding human IL-1RA. IL-1RA-expressing HSPCs engrafted, self-renewed and differentiated into all immune cell types with amplitude and kinetic similar to control mice. No microscopic abnormalities were observed in the immune and non-immune organs of chimeric mice, indicating that stable IL-1RA expression was well tolerated. Cell-mediated IL-1RA delivery significantly reduced acute neutrophil recruitment in response to crystal-mediated peritonitis to a similar extent as anakinra. In contrast, immune cell-derived IL-1RA was superior to anakinra in ameliorating the clinical phenotype of CAPS at both systemic and tissue levels. In addition, our approach significantly improved the clinical score and survival, and reduced immune cell infiltrates in the spinal cord of mice with EAE. Our results demonstrate that stable IL-1RA production by immune cells protects mice against IL-1-mediated inflammation in three experimental models, opening new therapeutic avenues for treating autoinflammatory diseases caused by IL-1 dysregulation.