IMPROVEMENT OF ANEMIA IN W W-V MICE BY RECOMBINANT-HUMAN-ERYTHROPOIETIN (RHUEPO) MEDIATED THROUGH EPO RECEPTORS WITH LOWERED AFFINITY/

We studied the the effects of recombinant human erythropoietin (rHuEPO ) on anemic W/W-v mice which manifested severe anemia accompanied by m utation of the W gene encoding tyrosine kinase type receptor (c-kit ge ne) of bone marrow hematopoietic cells. Nine-week-old male W/W-v mice or normal littermates (+/+) were used. Since serum EPO concentration i n W/W-v mice increased in proportion to severity of anemia, EPO produc tion in the kidneys of these animals was found to be regulated normall y. Hematocrit in +/+ mice increased and a maximal response was also ob tained with 2,000 IU/kg of rHuEPO. On the other hand, hematocrit in W/ W-v mice increased in a dose-responsive manner by administration with 2,000 and 10,000 IU/kg, showing different responses to rHuEPO in these two types of mice. The responsiveness of W/W-v mice to rHuEPO was low in terms of increases in erythroblastic precursor cells (CFU-E), and immature cells in the bone marrow. Scatchard analysis of the specific binding of I-125-rHuEPO against bone marrow cells revealed that the di fferent responsiveness to rHuEPO between W/W-v and +/+ mice may be cor related with differences in affinity of EPO receptor of bone marrow ce lls in these mice. From these results, a high dose of rHuEPO is capabl e of improving the anemia in W/W-v mice that had EPO receptors with lo wered affinity, indicating the possible effectiveness of rHuEPO in ane mic patients with EPO receptor abnormality.