IN VIVO EFFECTS OF THE IMMUNOSUPPRESSANT 15-DEOXYSPERGUALIN ON HEMATOPOIESIS IN MURINE ALLOGENEIC BONE MARROW CHIMERAS; Its Thrombopoietic Activity and Reversal of Adverse Effects with Granulocyte Colony-Stimulating Factor and/or Erythropoietin1

Abstract

When 15-deoxyspergualin (DSG), a potent immunosuppressant, was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 14 to day 25, increased thrombopoiesis was induced on day 20 to day 33, accompanied by marked leukocytopenia and anemia. The mean platelet counts in DSG-treated and control [BALB/c-->C3H/He] bone marrow chimeras on day 25 were (114.1 +/- 0.5) x 10(4)/microliter versus (58.6 +/- 2.6) x 10(4)/microliter (1.9-fold increase). Colony-forming units-megakaryocyte (CFU-Meg) were not significantly increased in DSG-treated bone marrow chimeras. Colony-forming units-granulocyte/macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E) were decreased during DSG-treatment whereas CFU-Mix colony formations were rather increased, and more primitive hematopoietic progenitor cells (highly proliferative potential colony-forming units [CFU-HPP]) were not decreased in the same time period. Since CFU-GM and BFU-E colony formations were increased immediately after the cessation of DSG treatment, followed by the rebound of leukocyte counts and the recovery of hemoglobin (Hb) levels, the leukocytopenia and anemia appeared to be induced by a cytostatic effect of DSG. The adverse effect of DSG was partly reversed by the simultaneous administration of granulocyte colony-stimulating factor (G-CSF) and/or erythropoietin (EPO), suggesting the need for the administration of these cytokines in the case of bone marrow transplants treated with DSG. Furthermore, it was of note that DSG modulated hematopoiesis and stimulated the production of thrombopoietin (TPO)-like cytokine(s) as well as interleukin-3 (IL-3).