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

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

doi:10.1016/j.healun.2017.03.004

Cited by 14 publications

(18 citation statements)

References 50 publications

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“…Direct comparison of our results with previous reports appears difficult, as we transplanted donor hearts cervically 21,22 and not heterotopically 17,19. Whereas others applied multiple dosages of CTLA4-Ig resulting in survival times of 30 or 60 days for cardiac grafts,17,19 we administered only 1 single application of CTLA-4 Ig at d2 posttransplantation, which led to a mean survival of 50 days 22.…”

Section: Discussionmentioning

confidence: 75%

“…It has been demonstrated that the neutralization of NKG2D in combination with co-stimulation blockade results in prolonged cardiac graft survival 17,19. We therefore transplanted BALB/c-derived hearts into either C57BL/6 or Klrk1 -/- mice receiving a single dose of abatacept at d2 posttransplantation 22. Surprisingly, whereas co-stimulation blockade resulted in a median survival of 50 days in wildtype animals, Klrk1 -/- mice treated with abatacept displayed significantly reduced graft survival (median survival: 27 days; P = .0015).…”

Section: Resultsmentioning

confidence: 99%

“…Mononuclear cells (MNCs) from spleen, lymph nodes, and allografts were isolated as previously described 22. For flow cytometry, 1 × 10 6 cells were pre-incubated with FcR-blocking reagent (Miltenyi Biotech, Bergisch-Gladbach, Germany) for 15 minutes and afterwards stained with combinations of antibodies listed in Table 1.…”

Section: Animals and Methodsmentioning

confidence: 99%

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Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts

Fabritius

Ritschl

Resch

et al. 2017

American Journal of Transplantation

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It has already been shown that neutralization of the activating NK cell receptor NKG2D in combination with co-stimulation blockade prolongs graft survival of vascularized transplants. In order to clarify the underlying cellular mechanisms, we transplanted complete MHC-disparate BALB/c-derived cardiac grafts into C57BL/6 wildtypes or mice deficient for NKG2D (Klrk1 −/− ). Although median survival was 8 days for both recipient groups, we detected already at day 5 posttransplantation significantly greater intragraft frequencies of NKp46 + NK cells in Klrk1 −/− recipients than in wildtypes. This was followed by a significantly greater infiltration of CD4 + , but a lesser infiltration of CD8 + T cell frequencies. Contrary to published observations, co-stimulation blockade with CTLA4-Ig resulted in a significant acceleration of cardiac rejection by Klrk1 −/− recipients, and this result was confirmed by applying a neutralizing antibody against NKG2D to wildtypes. In both experimental setups, grafts derived from Klrk1 −/− recipients were characterized by significantly higher levels of interferon-γ mRNA, and both CD4 + and CD8 + T cells displayed a greater capacity for degranulation and interferon-γ production. In summary, our results clearly illustrate that NKG2D expression in the recipient is important for cardiac allograft survival, thus supporting the hypothesis that impairment of NK cells prevents the establishment of graft acceptance.

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Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

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Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts

Fabritius

Ritschl

Resch

et al. 2017

American Journal of Transplantation

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“…In line, the administration of iron isomaltoside had consistent yet not significant effects on effector/ memory tumor infiltrating lymphocyte populations. In contrast, numbers of FoxP3 + CD4 + Tregs were comparable across treatment arms suggesting that the adverse effects of iron towards effector T cell populations where direct rather than indirect and Treg-mediated (72,73).…”

Section: Discussionmentioning

confidence: 92%

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

et al. 2020

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Iron is both, an essential compound for many metabolic processes, and iron deficiency can impact on the proliferation of cells including lymphocytes but also tumor cells. On the other hand, excess iron-catalyzed radical formation can induce cellular toxicity which has been previously demonstrated for T cells in hereditary iron overload. Despite these interconnections, little is known on the effects of clinically approved intravenous iron supplements for curing cancer-related anemia, on T cell differentiation, tumor proliferation, anti-tumor T cell responses and, of clinical importance, on efficacy of cancer immunotherapies. Herein, we analyzed the effects of intravenous iron supplementation on T cell function and on the effectiveness of anti-cancer chemotherapy with IL-2/doxorubicin or immunotherapy with checkpoint-inhibitor anti-PD-L1 in C57Bl/6N female mice with implanted E0771 mammary carcinomas. We found that iron application resulted to an increased availability of iron in the tumor microenvironment and stimulation of tumor growth. In parallel, iron application inhibited the activation, expansion and survival of cytotoxic CD8+ T cells and of CD4+ T helper cells type 1 and significantly reduced the efficacy of the investigated anti-cancer treatments. Our results indicate that iron administration has a tumor growth promoting effect and impairs anti-cancer responses of tumor infiltrating T lymphocytes along with a reduced efficacy of anti-cancer therapies. Iron supplementation in cancer patients, especially in those treated with immunotherapies in a curative setting, may be thus used cautiously and prospective studies have to clarify the impact of such intervention on the outcome of patients.

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“…This is particularly concerning because of the interaction of iron with allo‐immune response and in view of emerging evidence that suggests a potential role for iron in the ischaemia–reperfusion injury of the graft. The evidence even suggests that disturbance in iron homeostasis could affect graft survival and risk of rejection after heart transplantation …”

Section: Is Intravenous Iron Supplementation In Patients With Hfref Amentioning

confidence: 99%

Intravenous iron therapy in heart failure: a different perspective

Ghafourian

Chang

Ardehali

2019

European J of Heart Fail

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

Abstract: 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.

Cited by 14 publications

References 50 publications

Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts

Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

Intravenous iron therapy in heart failure: a different perspective

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