STEM-CELL RESPONSES IN MYELOSUPPRESSED MICE FOLLOWING SEQUENTIAL TREATMENT WITH RECOMBINANT HUMAN INTERLEUKIN-1 (RHUIL-1), RECOMBINANT MURINE INTERLEUKIN-3 (RMUIL-3) AND RECOMBINANT HUMAN MACROPHAGE-COLONY-STIMULATING FACTOR (RHUM-CSF)

In vivo, recombinant human interleukin 1 alpha (rHuIL-1 alpha) + recom binant human macrophage felony-stimulating factor (rHuM-CSF) (IL-1 + M -CSF) effectively serves as a rescue agent for myelosuppression by enh ancing the recovery of hematopoietic stem cell (HSC) subpopulations fo llowing treatment with 5-fluorouracil (5-mT). Because in vitro studies have suggested that hematopoietic recovery in 5-FU-treated bone marro w (FUBM) may proceed from a 5-FU resistant, (IL-1 + IL-3 + M-CSF-respo nsive) high proliferative potential HSC subpopulation of colony formin g cells (HCPP-CFC), studies were carried out to determine whether the addition of recombinant murine interleukin 3 (rMuIL-3) (IL-3) to eithe r IL-1 or IL-1+ M-CSF would further enhance the recovery of HSC subpop ulations in myelosuppressed C57B1/6 mice. With the exception of the HP P-CFC, IL-3 dampened, rather than enhanced, the accelerated recovery o f 8 d and 12 d colony forming units-spleen (8 d and 12 d CFU-S) and th e committed macrophage progenitor (CFU-M) associated with in vivo trea tment with IL-1 alone. Similarly, IL-3 interfered with the enhanced re covery of those HSC subpopulations in FUBM influenced by the synergist ic interaction of IL-1+ M-CSF. This interference, however, was observe d only when the rMuIL-3 was administered on day 2 or 3 of a four-day t reatment with IL-1 + M-CSF. There was, however, no evidence that IL-3 exerted a negative influence on the restoration of granulocytes in the myelosuppressed animals. Moreover, sequencing studies provided data s uggesting that the dampening effects of IL-3 on the synergistic intera ction of IL-1+ M-CSF resulted from both an enhanced differentiation of the more primitive HSC subpopulations and a significant, but preferen tial, mobilization of the more mature 8 d CFU-S and CFU-M to extramedu llary organs and that the mobilization of these more mature HSC subpop ulations was temporally linked to their generation from the recovering HPP-CFC and 12 d CFU-S subpopulations.