"The earliest currently identifiable process in the pathogenesis of type 1 diabetes (T1D) is the development of autoimmunity to islet beta cells in the form of autoantibodies. Hindering attempts to prevent autoimmune T1D, the aetiology and pathogenesis of the islet auto-immunization, including whether it is preceded by metabolic abnormalities and cell-mediated autoimmunity, is still poorly understood. To overcome this, DIAPREPP will focus on the early auto-immunization against islet antigens, in particular to disclose events preceding current autoantibody markers. The concept is that events prior to auto-immunization govern the likelihood and ‘signature’ of immunization, which in turn determines progression to disease. The overall objective is to determine mechanisms of islet autoantigen immunization. In a truly collaborative manner, and through five S/T workpackages plus three dedicated to dissemination, training, and management, DIAPREPP will 1. provide a unique set of clinical material that includes a case-control cohort representative of the world’s largest studies of pre-T1D, with follow-up and samples from birth, and pancreatic islets and lymph nodes from patients; 2. investigate the effects of environmental exposure to infections on islet cells and immune cells; 3. perform extensive metabolomic analysis of pre-autoimmune samples and in relevant animal models to test mechanistic hypotheses of auto-immunization; 4. carry out detailed analyses of early autoimmune responses with a special focus on autoreactive CD8+ T cells; and 5. apply findings to ongoing prevention studies. The expected impact of DIAPREPP is new fundamental knowledge regarding how 1. immunization against islet autoantigens can occur; 2. signs of self-immunization can be exploited for prediction and monitoring of disease; and 3. the immunization or its progression to islet beta cell destruction and T1D development can be prevented."