Background: Clinical data suggest that iron (Fe) overload deleteriously affects graft survival after heart (HTX) and kidney transplantation (KTX) but possible immunologic mechanisms underlying this phenomenon have not been elucidated.

Methods: To identify the mechanistic influence of Fe in a murine model of HTX or KTX, fully allogeneic Balb/C donor organs were transplanted into Fe overloaded C57BL/6 recipients. At day 5 (HTX) and 7 (KTX) various lymphocyte subsets were analyzed by flow cytometry. Inflammatory and Fe parameters were assessed by RT-PCR and histology.

Results: Following HTX, Fe overload accelerated rejection as observed by a shortened graft survival (HTX: 8.5 vs. HTX+Fe: 7.5 days; p<0.05) and elevated ISHLT-rejection score (HTX: 1.4 vs. HTX+Fe: 2.5; p<0.01). Whereas a pronounced graft infiltration of CD4⁺ T (HTX: 2.1±0.2% vs. HTX+Fe: 6±1.2%; p<0.01) and CD3^–NKp46⁺ NK cells (11.9±3.3% vs. 19.4±1.4%; p<0.05) was observed, reduced frequencies of regulatory subtypes were detected in graft (CD25⁺ T_Reg subset of CD3⁺CD4⁺ cells: HTX: 8.2±1.4% vs. HTX+Fe: 1.9±0.3%) and spleen (CD25⁺FOXP3⁺ T_Reg subset: HTX: 3.8±0.3% vs. HTX+Fe: 0.6±0.08%) (p<0.01 respectively) which was accompanied by a simultaneous down modulation of intra-graft expression of anti-inflammatory cytokines (IL-10, TGF-beta) and FoxP3. Following KTX, analogous observations were retrieved analyzing NK cells, CD4⁺ lymphocytes and T_Reg cells (all p<0.01). Moreover, whereas HTX and KTX per se activated splenic NK cells towards a mature CD11b⁺CD27⁺ phenotype, this effect was even more accentuated following Fe overload. Interestingly, assessment of hepcidin, CD71 and ferroportin expression revealed a significant induction in heart and kidney grafts, suggesting that the allograft itself – initially derived from a healthy donor – is affected by the Fe overload of the recipient.

Conclusion: We show for the first time that Fe overload in the recipient results in accelerated graft rejection via activation of NK, CD4⁺ T and depletion of T_Reg cells – independently of the experimental model (HTX, KTX). The functional influence of Fe on components of the immune system requires further investigation in order to understand its detailed impact on tolerance, infections or allograft survival.

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