Marked improvement of thrombocytopenia in a murine model of idiopathic thrombocytopenic purpura by pegylated recombinant human megakaryocyte growth and development factor
Received 5 March 2002; received in revised form 11 June 2002; accepted 13 June 2002.
Abstract
Objective
We examined the stimulatory effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production in male (NZW × BXSB) Fl (W/B F1) mice, a murine model of idiopathic thrombocytopenic purpura.
Materials and Methods
A cohort of 19- to 25-week-old, severely thrombocytopenic male W/B F1 mice were given PEG-rHuMGDF at different dosing schedules. Before and at various times after therapy, platelet counts, reticulated platelets, platelet lifespan, and levels of platelet-associated immunoglobulin G were measured. Analysis of megakaryocytic cells was performed.
Results
Treatment of male W/B F1 mice with PEG-rHuMGDF (30 μg/kg/day) three times per week for several weeks resulted in sustained thrombocytosis, accompanied by increased megakaryocytopoiesis in both the bone marrow and spleen. The degree of the platelet response to PEG-rHuMGDF varied between individual mice, likely reflecting the heterogeneity of the disease. Production of new platelets in response to PEG-rHuMGDF was manifested by an increase in reticulated platelets. Levels of platelet-associated immunoglobulin G decreased inversely during periods of thrombocytosis. PEG-rHuMGDF therapy also improved thrombocytopenia in male W/B F1 mice refractory to splenectomy. Platelet lifespan was not affected by PEG-rHuMGDF. Male W/B F1 mice treated with pegylated murine MGDF, a homologue of PEG-rHuMGDF, had persistent thrombocytosis for at least 7 months, suggesting that antiplatelet antibody production was not enhanced.
Conclusion
PEG-rHuMGDF therapy potently stimulated platelet production, effectively ameliorating thrombocytopenia in a murine model of idiopathic thrombocytopenic purpura.
aPharmaceutical Development Laboratory, Kirin Brewery Company, Ltd., Gunma, Japan
bPharmaceutical Research Laboratory, Kirin Brewery Company, Ltd., Gunma, Japan
Offprint requests to: Hiroshi Miyazaki, Ph.D., Pharmaceutical Development Laboratory, Kirin Brewery Company, Ltd., 3 Miyahara-cho, Takasaki, Gunma 370-1295, Japan
ABSTRACT