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