Thomas Resch1, Muhammad Imtiaz Ashraf2, Paul Viktor Ritschl2, Susanne Ebner1, Cornelia Fabritius1, Andrea Brunner3, Georg Schäfer3, Heinz Regele4, Julia Günther1, Günter Weiss5, Katja Kotsch6. 1. Department of Visceral, Abdominal and Transplantation Surgery, Medical University of Innsbruck, Innsbruck, Austria. 2. Department of Surgery, Charité-Universitätsmedizin, Berlin, Germany. 3. Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria. 4. Clinical Department of Pathology, Medical University of Vienna, Vienna, Austria. 5. Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria. 6. Department of Surgery, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: katja.kotsch@charite.de.
Abstract
BACKGROUND: Clinical data suggest that iron disturbances deleteriously affect graft survival after heart transplantation (HTx), but immunological mechanisms underlying this phenomenon have not yet been elucidated. METHODS: To identify the mechanistic influence of iron in a murine model of HTx, fully allogeneic BALB/c donor organs were transplanted into iron-overloaded or iron-deficient C57BL/6 mice, and recipients were analyzed for functional and immunological parameters. RESULTS: After HTx, iron overload accelerated acute rejection as observed by shortened graft survival (HTx vs HTx + iron; p = 0.01), elevated rejection score (p < 0.01), and induction of troponin T (p < 0.01). Compared with controls, allografts and recipient spleens derived from iron-overloaded recipients were characterized by a pronounced graft infiltration of CD4+ T cells (p < 0.01), CD3-NKp46+ natural killer cells (p < 0.05), and reduced frequencies of regulatory T cells (p < 0.01). This was accompanied by lower mRNA expression levels of anti-inflammatory cytokines, including interleukin-10, transforming graft factor-β, and Foxp3. Cardiac allograft survival was further tested under co-stimulation blockade (CTLA4-Ig) showing that naïve grafts transplanted into iron-overloaded recipients illustrated restricted graft outcome compared with wild types (p = 0.0051), which was rescued after treatment with the iron chelator deferoxamine. Iron deficiency (ID) also resulted in enhanced intragraft infiltration of inflammatory cells and accelerated rejection in the acute setting (HTx vs HTx + ID; p = 0.02) and after co-stimulation blockade (p = 0.0059). CONCLUSIONS: We provide novel insights into the understanding of disturbances in iron homeostasis and their consequences after HTX, allowing novel insights regarding improvements in personalized immunosuppression to prolong allograft survival.
BACKGROUND: Clinical data suggest that iron disturbances deleteriously affect graft survival after heart transplantation (HTx), but immunological mechanisms underlying this phenomenon have not yet been elucidated. METHODS: To identify the mechanistic influence of iron in a murine model of HTx, fully allogeneic BALB/c donor organs were transplanted into iron-overloaded or iron-deficient C57BL/6 mice, and recipients were analyzed for functional and immunological parameters. RESULTS: After HTx, iron overload accelerated acute rejection as observed by shortened graft survival (HTx vs HTx + iron; p = 0.01), elevated rejection score (p < 0.01), and induction of troponin T (p < 0.01). Compared with controls, allografts and recipient spleens derived from iron-overloaded recipients were characterized by a pronounced graft infiltration of CD4+ T cells (p < 0.01), CD3-NKp46+ natural killer cells (p < 0.05), and reduced frequencies of regulatory T cells (p < 0.01). This was accompanied by lower mRNA expression levels of anti-inflammatory cytokines, including interleukin-10, transforming graft factor-β, and Foxp3. Cardiac allograft survival was further tested under co-stimulation blockade (CTLA4-Ig) showing that naïve grafts transplanted into iron-overloaded recipients illustrated restricted graft outcome compared with wild types (p = 0.0051), which was rescued after treatment with the iron chelator deferoxamine. Iron deficiency (ID) also resulted in enhanced intragraft infiltration of inflammatory cells and accelerated rejection in the acute setting (HTx vs HTx + ID; p = 0.02) and after co-stimulation blockade (p = 0.0059). CONCLUSIONS: We provide novel insights into the understanding of disturbances in iron homeostasis and their consequences after HTX, allowing novel insights regarding improvements in personalized immunosuppression to prolong allograft survival.
Authors: Cornelia Fabritius; Paul Viktor Ritschl; Thomas Resch; Mario Roth; Susanne Ebner; Julia Günther; Vanessa Mellitzer; Anh-Vu Nguyen; Johann Pratschke; Martina Sauter; Karin Klingel; Katja Kotsch Journal: Am J Transplant Date: 2017-09-09 Impact factor: 8.086
Authors: Joanna Sophia J Vinke; Marith I Francke; Michele F Eisenga; Dennis A Hesselink; Martin H de Borst Journal: Nephrol Dial Transplant Date: 2021-11-09 Impact factor: 5.992
Authors: Kristine V Brautaset Englund; Charlotte M Østby; Kaspar Broch; Thor Ueland; Pål Aukrust; Einar Gude; Arne K Andreassen; Lars Gullestad Journal: Clin Transplant Date: 2022-06-01 Impact factor: 3.456