Fernandes J C, Garrido P, Ribeiro S, Rocha-Pereira P, Bronze-da-Rocha E, Belo L, Costa E, Reis F, Santos-Silva A
Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal ; Institute for Molecular and Cellular Biology, University of Porto, 4150-180 Porto, Portugal.
Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, . 3000-548 Coimbra, Portugal.
Biomed Res Int. 2014;2014:421304. doi: 10.1155/2014/421304. Epub 2014 Dec 18.
Erythroid hypoplasia (EH) is a rare complication associated with recombinant human erythropoietin (rHuEPO) therapies, due to development of anti-rHuEPO antibodies; however, the underlying mechanisms remain poorly clarified. Our aim was to manage a rat model of antibody-mediated EH induced by rHuEPO and study the impact on iron metabolism and erythropoiesis. Wistar rats treated during 9 weeks with a high rHuEPO dose (200 IU) developed EH, as shown by anemia, reduced erythroblasts, reticulocytopenia, and plasmatic anti-rHuEPO antibodies. Serum iron was increased and associated with mRNA overexpression of hepatic hepcidin and other iron regulatory mediators and downregulation of matriptase-2; overexpression of divalent metal transporter 1 and ferroportin was observed in duodenum and liver. Decreased EPO expression was observed in kidney and liver, while EPO receptor was overexpressed in liver. Endogenous EPO levels were normal, suggesting that anti-rHuEPO antibodies blunted EPO function. Our results suggest that anti-rHuEPO antibodies inhibit erythropoiesis causing anemia. This leads to a serum iron increase, which seems to stimulate hepcidin expression despite no evidence of inflammation, thus suggesting iron as the key modulator of hepcidin synthesis. These findings might contribute to improving new therapeutic strategies against rHuEPO resistance and/or development of antibody-mediated EH in patients under rHuEPO therapy.
红细胞生成低下（EH）是与重组人促红细胞生成素（rHuEPO）治疗相关的一种罕见并发症，这是由于抗rHuEPO抗体的产生；然而，其潜在机制仍不清楚。我们的目的是建立一个由rHuEPO诱导的抗体介导的EH大鼠模型，并研究其对铁代谢和红细胞生成的影响。用高剂量rHuEPO（200 IU）治疗9周的Wistar大鼠出现了EH，表现为贫血、成红细胞减少、网织红细胞减少和血浆抗rHuEPO抗体。血清铁增加，并与肝脏铁调素和其他铁调节介质的mRNA过表达以及matriptase-2的下调相关；在十二指肠和肝脏中观察到二价金属转运体1和铁转运蛋白的过表达。在肾脏和肝脏中观察到EPO表达降低，而EPO受体在肝脏中过表达。内源性EPO水平正常，提示抗rHuEPO抗体减弱了EPO功能。我们的结果表明，抗rHuEPO抗体抑制红细胞生成导致贫血。这导致血清铁增加，尽管没有炎症证据，但似乎刺激了铁调素的表达，因此提示铁是铁调素合成的关键调节因子。这些发现可能有助于改进针对rHuEPO抵抗和/或接受rHuEPO治疗患者中抗体介导的EH的新治疗策略。
