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) prominently stimulates hematopoietic reconstitution following myelosuppressive treatment and potentiates the efficacy of both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). However, TPO alone is not effective after bone marrow transplantation. Based on results of GM-CSF and TPO treatment after myelosuppression that resulted in augmented thrombocyte, reticulocyte, and leukocyte regeneration, we evaluated TPO/GM-CSF treatment after lethal irradiation followed by autologous bone marrow transplantation.

MATERIALS AND METHODS

Young adult Rhesus monkeys were subjected to 8-Gy total body irradiation (TBI) (x-rays) followed by transplantation of 10(7)/kg unfractionated bone marrow cells. TPO 5 microg/kg was administered intravenously at day 0 to obtain rapidly high levels. Animals then were treated with 5 microg/kg Rhesus TPO and 25 microg/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 significantly influence the recovery patterns of thrombocytes (p = 0.39), reticulocytes (p = 0.08), white blood cells (p = 0.08), or bone marrow progenitors compared to TPO alone.

CONCLUSIONS

The present study demonstrates that, after high-dose TBI and transplantation of a limited number of unfractionated bone marrow cells, simultaneous administration of TPO and GM-CSF after TBI is ineffective in preventing pancytopenia. This result contrasts sharply with the prominent stimulation observed in a 5-Gy TBI myelosuppression model, despite a similar level of pancytopenia in the 8-Gy model of the present study. The discordant results of this growth factor combination in these two models may imply codependence of the hematopoietic response to TPO and/or GM-CSF on other factors or cytokines.