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Transferrin therapy ameliorates disease in β -thalassemic mice

Transferrin therapy ameliorates disease in β -thalassemic mice. Alisha Juman Lakeland High School Grade 10. Li H, Rybicki AC, Suzuka SM, et al. Nat Med. 2010 Jan 24; 16(2):177-82. Introduction. β -thalassemias are caused by mutations in gene encoding beta-globin (Weatherall et al., 1998)

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Transferrin therapy ameliorates disease in β -thalassemic mice

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  1. Transferrin therapy ameliorates disease in β-thalassemic mice Alisha Juman Lakeland High School Grade 10 Li H, Rybicki AC, Suzuka SM, et al. Nat Med. 2010 Jan 24; 16(2):177-82

  2. Introduction • β-thalassemias are caused by mutations in gene encoding beta-globin (Weatherall et al., 1998) • Excess alpha-globin (α-globin) results in increased erythroid precursor apoptosis, causing ineffective erythropoiesis, extramedullary expansion, and splenomegaly (Pootrakul et al., 1988) • Along with shortened red blood cell (RBC) survival, these conditions result in anemia (Centis et al., 2000)

  3. Hepcidin, produced by the liver, regulates iron absorption and recycling • In the case of β-thalassemia, hepcidin concentrations are low (Papanikolaou et al., 2005) • Transferrin functions as the main transporter of iron in the circulation • Patients with -thalassemia can develop iron overload beyond the iron-binding capacity of transferrin • In this case, labile plasma iron (LPI) can be found in the circulation, causing damage resulting in morbidity (Esposito et al., 2003)

  4. Ginzburg et al. (2010) demonstrated that in Hbb th1/th1 mice treated with iron, iron induced extramedullary, not medullary erythroid expansion • Ineffective delivery of iron to the bone marrow may be an explanation • Hypothesized that inability to compensate for ineffective erythropoiesis and anemia in β-thalassemic mice, is in part a result of an insufficient amount of circulating transferrin

  5. Objective • To increase the amount of transferrin to accommodate the expansion of erythropoiesis in Hbb th1/th1 mice, a commonly used mouse model of β-thalassemia intermedia

  6. Methods • Hbb th1/th1 (thalassemic) mice bred from parental stock and backcrossed for 11 generations onto a C57/BL6 background • Both thalassemic mice and WT control mice were bred • Performed intraperitoneal injections for a total of 60 days • Optimum dose presumed to be 10 mg of transferrin per day • Apotransferrin and holotransferrin were prepared from human plasma

  7. Results • Initially treated mice for a 10 day course • Extended treatment to 60 days • LPI levels were higher in thalassemic mice, but transferrin injections returned LPI levels to normal , while also increasing the total iron binding capacity (TIBC) • Partial reversal of anemia with fewer reticulocytes • Transferrin treated mice showed a higher number of RBCs, more abundant hemoglobin, and lower reticulocyte count

  8. Reversed splenomegaly and extramedullary erythropoiesis • Injection resulted in a reduction in spleen size and weight, with more organized “splenic” architecture • Findings show that transferrin treatment reduced extramedullary erythropoiesis in both the spleen and liver • Shift in maturation and apoptosis of erythroid cells • Found that the distribution of erythroid precursors in the spleen and bone marrow shifted to a higher proportion of mature relative to immature cells • Hepcidin expression increased in the livers of treated thalassemic mice, while no difference in hepcidin expression was observed in WT mice

  9. Discussion • The results of increasing the amount of circulating transferrin serves to support the hypothesis • Injections increased RBC survival and circulating hemoglobin concentrations, and decreased reticulocytosis, splenomegaly, and circulation of LPI • Reduction of α-globin resulted in an increased RBC survival

  10. Since splenomegaly is often associated in worsening anemia, its reversal is a possible cause of increased hemoglobin levels • Enlarged spleen, which is a site for extramedullary erythropoiesis, was most likely transformed due to decrease in extramedullary erythropoiesis • Significance of research: • Transferrin treatment significantly decreased apoptosis of mature RBCs in spleen, increased apoptosis of immature RBCs, and increased expression of hepcidin

  11. Further Research • Evidence of an “erythroid regulator” of hepcidin due to decreased extramedullary erythropoiesis caused by increase in hepcidin expression • Evaluation of growth differentiation factor 15 (GDF15) and the twisted gastrulation factor (TWSG1) is needed to clarify underlying mechanisms • Suggest that transferrin purified from human donors may have several potential uses • Treating diseases of concurrent anemia and iron overload • Treatment would first be administered to patients with β-thalassemia disease

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