Preclinical studies on synergistic effects of IL-1, IL-3, G-CSF and GM-CSF in cynomolgus monkeys

Abstract

The regulation of blood cell formation is mediated by a group of polypeptides classified as hematopoietic growth and differentiation factors. Overlapping as well as distinct functions have been described for three of these cytokines: interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Furthermore, interleukin 1 (IL-1) has been shown to promote hematopoietic regeneration after cytoreductive drug treatment. Evidence has been provided by in vitro studies that combinations of these factors exert a highly synergistic action on the proliferation and differentiation of committed hematopoietic progenitor cells. Additionally, these findings have been supported by studies of in vivo blood cell formation in nonhuman primates. We report here that IL-3 acts synergistically with GM-CSF or G-CSF on myelocytic cell development only if an administration time of eight days of IL-3 is followed by GM-CSF or G-CSF. Short-time IL-3 application of two and four days only resulted in platelet production. The reverse administration schedule did not show synergistically enhanced stimulation of myelocytic cells. However, G-CSF treatment followed by IL-3 did induce a two-fold increase in platelet numbers. This would appear to confirm previously reported in vitro findings that G-CSF shortens the G0 period of human hematopoietic stem cells, which subsequently proliferate in the presence of IL-3. The effects of IL-3 on myelocytic and megakaryocytic development seems to be differently regulated. Whereas, IL-1 failed to display synergistic activity with GM-CSF or G-CSF is sequentially applied. Only simultaneous application either in combination with GM-CSF or with G-CSF demonstrated enhanced efficacy.