title: Disturbances in iron homeostasis result in accelerated rejection after experimental heart transplantation.
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.
authors.affiliation: Department of Visceral, Abdominal and Transplantation Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Resch
authors.affiliation: Department of Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Muhammad Imtiaz
authors.initials: MI
authors.lastname: Ashraf
authors.affiliation: Department of Surgery, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Paul Viktor
authors.initials: PV
authors.lastname: Ritschl
authors.affiliation: Department of Visceral, Abdominal and Transplantation Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ebner
authors.affiliation: Department of Visceral, Abdominal and Transplantation Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Fabritius
authors.affiliation: Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brunner
authors.affiliation: Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.affiliation: Clinical Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Regele
authors.affiliation: Department of Visceral, Abdominal and Transplantation Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Günther
authors.affiliation: Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Department of Surgery, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: katja.kotsch@charite.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D006706:Homeostasis; D019189:Iron Metabolism Disorders / Q000150:complications*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines
keywords: heart transplantation; inflammation; iron chelation; iron homeostasis; rejection