Disturbances in iron homeostasis result in accelerated rejection after experimental heart transplantation

Thomas Resch; Muhammad Imtiaz Ashraf; Paul Viktor Ritschl; Susanne Ebner; Cornelia Fabritius; Andrea Brunner; Georg Schäfer; Heinz Regele; Julia Günther; Günter Weiss; Katja Kotsch

doi:10.1016/j.healun.2017.03.004

Disturbances in iron homeostasis result in accelerated rejection after experimental heart transplantation

J Heart Lung Transplant. 2017 Jul;36(7):732-743. doi: 10.1016/j.healun.2017.03.004. Epub 2017 Mar 7.

Affiliations

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.

PMID: 28372951
DOI: 10.1016/j.healun.2017.03.004

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.

Keywords: heart transplantation; inflammation; iron chelation; iron homeostasis; rejection.

MeSH terms

Animals
Cytokines / blood
Disease Models, Animal
Graft Rejection / etiology*
Graft Survival
Heart Transplantation / adverse effects*
Homeostasis
Iron Metabolism Disorders / complications*
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL

Substances

Cytokines