Disturbances in iron homeostasis result in accelerated rejection after experimental heart transplantation.
J Heart Lung Transplant
; 36(7): 732-743, 2017 Jul.
Article
en En
| MEDLINE
| ID: mdl-28372951
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-ß, 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trasplante de Corazón
/
Trastornos del Metabolismo del Hierro
/
Rechazo de Injerto
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Heart Lung Transplant
Asunto de la revista:
CARDIOLOGIA
/
TRANSPLANTE
Año:
2017
Tipo del documento:
Article
País de afiliación:
Austria