Mark Peakman1 and Pere Santamaria2,3 1Immunology and Inflammation Research Therapeutic Area, Sanofi, Cambridge, Massachusetts 02141, USA 2Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta T2N 4N1, Canada 3Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain Correspondence: mark.peakmansanofi.com; psantamaucalgary.ca

Type 1 diabetes (T1D) is driven by an immunologically complex, diverse, and self-sustaining immune response directed against tissue autoantigens, leading to loss or dysfunction of β cells. To date, the single approved immune intervention in T1D is based on a strategy that is similar to that used in other related autoimmune diseases, namely, the attenuation of immune cell activation. As a next-generation approach that is more focused on underlying mechanisms of loss of tolerance, antigen-specific immunotherapy is designed to establish or restore bystander immunoregulation in a highly tissue- and target-specific fashion. Here, we describe the basis for this alternative approach, which could also have potential for complementarity if used in combination with more conventional immune modulators, and highlight recent advances, knowledge gaps, and next steps in clinical development.