This proposal will pioneer the concept of tailored interventions with minimal immune system interference in new onset T1DM, leading to beta-cell protection and restoration, based on a solid understanding of the disease pathogenesis. This will enable experimental findings to be adopted for future clinical application. Four work packages are grouped around ‘Reversal of autoimmunity’, in which two key players of the immune system in beta-cell destruction will be targeted: the dendritic cell (WP1: Re-educating antigen-presenting cells) and the T-lymphocyte (WP2: Restoring the T-cell balance). In both cell types, interventions using steroid hormones (vitamin D and glucocorticoids) will be used to induce tolerance. Moreover, novel interventions using soluble T-cell receptors to target immune cells and beta-cells in an antigen-specific way (WP3: TCR-mediated immunotherapy) will be introduced. Novel mucosal interventions using probiotics and recombinant L. lactis as a carrier for specific peptides in combination with cytokines (WP4: Mucosal intervention for tolerance restoration) will be studied for their immune modulating potential. A full work package (WP5: Beta-cell protection and restoration – the dialogue with the immune system) is dedicated to the beta-cell and its role in driving and amplifying the immune attack through communication between beta-cells and the immune system. The last scientific work package (WP6: Pharmacogenetics) will identify genetic profiles within patients that predict responsiveness to the steroid interventions proposed. WP7 and 8 are dedicated to training and management of the consortium. For this purpose, a multidisciplinary consortium of leading European diabetologists and immunologists from 11 academic research institutions, in co-operation with 3 SMEs developing novel technologies allowing translation of basic research results towards clinical applications, has been established.