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) 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)
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)
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
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
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
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
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
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
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
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