Mesenchymal stem cell (MSC) transplantation has been successfully used in autoimmune disorders, but has not been applied in granulomatosis with polyangiitis (GPA), the most common entity of anti- neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides. GPA is characterized by systemic autoimmune necrotizing vasculitis and chronic non-resolving granulomatous inflammation preferentially affecting the respiratory tract. Whereas necroinflammation, an autoamplificatory process driven by necrosis and cytokines, plays a pivotal role in the break of immune tolerance to PR3, fibroblast- mediated tissue destruction perpetuates chronic inflammation and necrosis in GPA. We hypothesize that MSC transplantation abrogates both fibroblast-mediated cartilaginous tissue damage and necroinflammation. To investigate the impact of MSCs on necroinflammation and fibroblast-mediated tissue destruction in GPA, MSC- induced modulation of inflammatory and destructive properties of fibroblasts and the effect of MSCs on regulated cell death of neutrophils will be analyzed in vivo using a previously established human cartilage and nasal mucosa-derived xenograft mouse model and ex vivo using co-culture systems. The in vitro capacity of bone marrow- and adipose tissue-derived MSCs on proinflammatory polarization of macrophages following phagocytosis of apoptotic neutrophils or PR3-transfected rat basophilic leukemia (RBL)-cells will be analyzed. Further, we shall investigate the cellular composition in the transplant depending on the MSCs used. Murine eGFP labelled MSCs will be used to trace the fate of the MSCs within the transplant and bone marrow, and adipose tissue MSCs will be used to investigate the composition of the infiltrating immune cells in order to determine if any of the two MSCs sources are superior to each other. Tissues generated in these experiments will be shared with Thomas Pap and Thomas Kamradt for further analysis of epigenetic aspects and cellular characterization. Our experiments address fundamental aspects of MSC-induced immunomodulatory effects on chronic inflammation and fibroblast-mediated tissue destruction relevant in GPA as well as in other autoimmune diseases.