title: Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbbth3/+ (heterozygous B1/B2 globin gene deletion) mice.
abstract: Intermediate beta-thalassemia has a broad spectrum of sequelae and affected subjects may require occasional blood transfusions over their lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron in plasma. The iron scavenger and transport protein transferrin is a potential treatment being studied for correction of anemia. However, transferrin may also function to prevent or reduce iron loading of tissues when exposure to non-transferrin bound iron increases. Here we evaluate the effects of apotransferrin administration on tissue iron loading and early tissue pathology in non-transfused and transfused Hbb(th3/+) mice. Mice with the Hbb(th3/+) phenotype have mild to moderate anemia and consistent tissue iron accumulation in the spleen, liver, kidneys and myocardium. Chronic apotransferrin administration resulted in normalization of the anemia. Furthermore, it normalized tissue iron content in the liver, kidney and heart and attenuated early tissue changes in non-transfused Hbb(th3/+) mice. Apotransferrin treatment was also found to attenuate transfusion-mediated increases in plasma non-transferrin bound iron and associated excess tissue iron loading. These therapeutic effects were associated with normalization of transferrin saturation and suppressed plasma non-transferrin bound iron. Apotransferrin treatment modulated a fundamental iron regulatory pathway, as evidenced by decreased erythroid Fam132b gene (erythroferrone) expression, increased liver hepcidin gene expression and plasma hepcidin-25 levels and consequently reduced intestinal ferroportin-1 in apotransferrin-treated thalassemic mice.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Center of Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, USA.
authors.forename: Monique P
authors.initials: MP
authors.lastname: Gelderman
authors.affiliation: Laboratory of Cellular Hematology, Center of Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, USA.
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Laboratory of Cellular Hematology, Center of Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, USA Division of Internal Medicine, University of Zurich, Switzerland.
authors.forename: Ayla
authors.initials: A
authors.lastname: Yalamanoglu
authors.affiliation: Functional Genomics Center Zurich, Swiss Federal Institute of Technology Zurich / University of Zurich, Switzerland Division of Internal Medicine, University of Zurich, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Puglia
authors.affiliation: Division of Internal Medicine, University of Zurich, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Vallelian
authors.affiliation: Division of Internal Medicine, University of Zurich, Switzerland.
authors.forename: Bo
authors.initials: B
authors.lastname: Burla
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Center of Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, USA.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Vostal
authors.affiliation: Division of Internal Medicine, University of Zurich, Switzerland Center of Evolutionary Medicine, University of Zurich, Switzerland.
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
authors.affiliation: Laboratory of Cellular Hematology, Center of Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, USA paul.buehler@fda.hhs.gov dominik.schaer@usz.ch.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000008:administration & dosage*; D001803:Blood Transfusion; D027682:Cation Transport Proteins / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004909:Erythrocyte Indices / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D064451:Hepcidins / Q000097:blood; D007501:Iron / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000188:drug therapy; D014168:Transferrin / Q000008:administration & dosage* / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics*; D000098742:Ferroportin
chemical_list: D001059:Apoproteins; D027682:Cation Transport Proteins; D016207:Cytokines; C572502:Erfe protein, mouse; D064451:Hepcidins; D009124:Muscle Proteins; D014168:Transferrin; C028284:apotransferrin; D055544:beta-Globins; D000098742:Ferroportin; D007501:Iron