Organ transplantation has emerged as the “gold standard” therapy for end-stage organ failure. Incomplete control of chronic allograft injury but also the adverse effects of long-term immunosuppression (IS) continue to challenge the long-term success of transplantation. The paradigm is shifting from increasing “net”-IS by novel drugs to the concept of minimizing long-term IS as early as possible. However, data were almost completely generated by “trial-and-error” observational studies. It suggests an unmet need to stratify transplant (Tx) patients regarding their immunological responsiveness to the allograft and their respective individual need of IS. The central focus of the project is the implementation of biomarker-driven strategies for personalizing IS to improve the long-term outcome and to decrease the adverse effects and costs of chronic IS. This includes 5 innovative investigator-driven biomarker clinical trials designed by the consortium with >1800 (screening) / 1000 (trial) patients. The following issues will be addressed: -targeted complete/partial weaning of standard IS in long-term stable liver and kidney Tx patients identified as “operationally tolerant” by recently developed biomarker panels-prevention of CNI-based standard IS in low-responder kidney Tx recipients by perioperative biomarker-based stratification-shifting high to low-responder kidney Tx patients suitable for early minimisation by the recently explored selective targeting of alloreactive effector/memory T cells -implementing new biomarker candidates supporting personalized IS within the clinical trials-analysing the health-economic impact of biomarker-guided personalized IS -studying the mechanisms behind successful weaning (regulation/effector balance) -disseminating the results and developing commercialisation by partnering with SME/industry. The project will take advantage and exploit recent research findings–Indices of Tolerance (IOT) and RISET but also of other international groups.