Lack of efficacy of thrombopoietin and granulocyte-macrophage colony-stimulating factor after total body irradiation and autologous bone marrow transplantation in Rhesus monkeys

Objective. If administered in a sufficiently high dose to overcome receptor -mediated clearance and in a well-scheduled manner, thrombopoietin (TPO) pr ominently stimulates hematopoietic reconstitution following myelosuppressiv e treatment and potentiates the efficacy of both granulocyte-macrophage col ony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor ( G-CSF), However, TPO alone is not effective after bone marrow transplantati on. Based on results of GM-CSF and TPO treatment after myelosuppression tha t resulted in augmented thrombocyte, reticulocyte, and leukocyte regenerati on, we evaluated TPO/GM-CSF treatment after lethal il radiation followed by autologous bone marrow transplantation. Materials and Methods. Young adult Rhesus monkeys were subjected to 8-Gy to tal body irradiation (TBI) (x-rays) followed by transplantation of 10(7)/kg unfractionated bone marrow cells. TPO 5 mu g/kg was administered intraveno usly at day 0 to obtain rapidly high levels. Animals then were treated with 5 mu g/kg Rhesus TPO and 25 mu g/kg GM-CSF given SC on days 1 to 14 after TBI. Results. The grafts shortened the profound pancytopenia induced by 8-Gy TBI from 5-6 weeks to 3 weeks. The combination of TPO and GM-CSF did not signi ficantly influence the recovery patterns of thrombocytes (p = 0.39), reticu locytes (p = 0.08), white blood cells (p = 0.08), or bone marrow progenitor s compared to TPO alone. Conclusions. The present study demonstrates that, after high-dose TBI and t ransplantation of a limited number of unfractionated bone marrow cells, sim ultaneous administration of TPO and GM-CSF after TBI is ineffective in prev enting pancytopenia. This result contrasts sharply with the prominent stimu lation observed in a 5-Gy TBI myelosuppression model, despite a similar lev el of pancytopenia in the 8-Gy model of the present study. The discordant r esults of this growth factor combination in these two models mag imply code pendence of the hematopoietic response to TPO and/or GM-CSF on other factor s or cytokines, (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.