Interstitial fibrosis and tubular atrophy (IF/TA) are major clinical challenges in kidney transplantation. Immunological knowledge on acute graft rejection and its clinical management have substantially improved, while the cumulative effects resulting in IF/TA- associated functional decline remain poorly understood. Systems medicine opens a new avenue towards unraveling these complex interactions involving chronic cellular and humoral rejection, interstitial inflammation, and macrophage-mediated tissue remodeling processes. Alternatively activated macrophages play a central role in this complex network of cellular interactions, regulating T-cell behavior in the tissue microenvironment, inducing tissue repair and remodeling effects, and conferring a delicate equilibrium between immunosuppressive beneficial and fibrosis-inducing detrimental effects. Sys-MIFTA will translate improved understanding of this network into tangible benefit for patients and cost-efficient, evidence-based use of currently emerging targeted immunomodulatory therapies. Key is integration of dynamic mathematical models of macrophage-associated immunological and metabolic regulation with advanced biopsy evaluation and ongoing clinical research to dissect processes in the renal interstitium that converge into IF/TA. Iterative model validation and improvement will be performed in the framework of a long standing protocol biopsy program and ongoing clinical studies. The interdisciplinary approach integrates systems immunology with advanced image analysis, digital pathology, basic immunology and clinical research. It will for the first time enable integration of advanced mathematical models and comprehensive digitally captured spatio-temporal information in clinical transplantation medicine. Sys-MIFTA paves the way towards innovative, participatory and predictive transplantation medicine, preventing morbidity and creating value by increasing efficacy of personalized immunomodulatory therapy.