title: Lack of efficacy of thrombopoietin and granulocyte-macrophage colony-stimulating factor after total body irradiation and autologous bone marrow transplantation in Rhesus monkeys.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Hematology, Erasmus University Rotterdam, The Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Hartong
authors.forename: K J
authors.initials: KJ
authors.lastname: Neelis
authors.forename: T P
authors.initials: TP
authors.lastname: Visser
authors.forename: G
authors.initials: G
authors.lastname: Wagemaker
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002469:Cell Separation; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D016131:Lymphocyte Subsets / Q000166:cytology; D008253:Macaca mulatta; D008297:Male; D013926:Thrombopoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D014916:Whole-Body Irradiation
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013926:Thrombopoietin