Abstract
Individuals with β-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in β-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbbth1/th1 mice, an experimental model of β-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human β-thalassemia.
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Acknowledgements
We extend special thanks to M. Knutson (University of Florida, Gainesville) for providing mouse antibodies to FPN-1, Jacobi Medical Center for sample analysis, T. Ganz, E. Nemeth and S. Rivella for stimulating discussions and R. Nagel and M. Narla for unparalleled guidance and support. This work was supported in part by contract grant sponsor US National Institutes of Health–National Heart, Lung, and Blood Institute number HL68962 and HL07556.
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H.L. collected and analyzed the data. A.C.R. analyzed and interpreted the data and revised the manuscript. S.M.S. provided the study material and technical support. L.v.B. provided the study material and logistical and technical support and revised the manuscript. W.B. provided experimental assistance. C.B.H. performed statistical analysis and revised the manuscript. Z.I.C. provided logistical support, interpreted the data and revised the manuscript. E.E.B. provided logistical support, interpreted the data and revised the manuscript. M.E.F. provided the study material and logistical support, interpreted the data and revised the manuscript. Y.Z.G. developed the idea and designed the experiments, collected, analyzed and interpreted the data and drafted and revised the manuscript.
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Li, H., Rybicki, A., Suzuka, S. et al. Transferrin therapy ameliorates disease in β-thalassemic mice. Nat Med 16, 177–182 (2010). https://doi.org/10.1038/nm.2073
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DOI: https://doi.org/10.1038/nm.2073
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