Stimulation of haematopoiesis in primates by continuous infusion of recombinant human GM-CSF

Abstract

Certain proteins are known to play an important part in the proliferation, differentiation and functional activation of haematopoietic progenitor cells in vitro. These proteins include erythropoietin and various colony-stimulating factors (CSFs), one of which is granulocyte-macrophage colony-stimulating factor (GM-CSF). Recently, both murine and human GM-CSF have been purified to homogeneity and complementary DNAs encoding them have been cloned. Although the in vitro activity of recombinant human GM-CSF has been investigated intensively, little is known about the functional activity of this protein in vivo. There is strong evidence that colony-stimulating activities produced by various human and murine tumour tissues and cell lines can stimulate granulopoiesis in mice, as can human urinary extracts. A partially purified preparation of human urinary colony-stimulating factor, however, proved only marginally effective in stimulating granulopoiesis in humans. All these studies suffer from the lack of a homogeneous preparation of colony-stimulating factor. It has recently been shown that recombinant murine multi-CSF or interleukin-3 can stimulate haematopoiesis in mice in vivo. Large-scale production of recombinant human GM-CSF now permits us to examine its effects in vivo using a primate model. We find that the continuous infusion of GM-CSF in healthy monkeys rapidly elicits a dramatic leukocytosis and a substantial reticulocytosis. A similar effect has been observed in one pancytopenic, immunodeficient rhesus macaque. These results suggest that GM-CSF could prove useful in several clinical situations.

Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions – a phase I dose-toxicity study

“…The triphasic rise of leucocytes seen during the 10-day administration of GM-CSF in this study was not observed in primates (Donahue et al, 1986) or humans with AIDS (Groopman et al, 1987) or myelodysplasia (Vadhan-Raj et al, 1987) who received prolonged administration of GM-CSF. The pattern of response is quite different from that seen with G-CSF (the other myeloid colony-stimulating factor undergoing clinical trials), which produces an immediate and sustained rise of the white cell count, presumably relating to its putative effect on later stages of commitment of granulocyte precursors (Bronchud et al, 1987).…”

“…Administration of GM-CSF to non-human primates results in the rapid onset of a leucocytosis, a similar response being obtained in a pancytopaenic, immunodeficient macaque (Donahue et al, 1986). Infusion of GM-CSF to primates undergoing total-body irradiation and infusion of autologous bone marrow accelerates haemopoietic recovery (Nienhuis et al, 1987).…”

Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin.

“…In vivo treatments with various cytokines, including G-CSF (21-23), GM-CSF (24,25), Kit ligand/stem-cell factor (26,27), IL-1 (28), and IL-11 (29), have shown that they all are capable of peripheralizing progenitors, but with different potencies and under different kinetics. Although the mechanism(s) ofcytokine-induced peripheralization ofprogenitors has not been elucidated, if overlapping mechanisms exist, one would not anticipate any additional mobilization by anti-VLA4 treatment.…”

In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients

“…Stimulation of granulopoiesis in vivo by recombinant human granulocyte colony-stimulating factor (rhG-CSF, Souza et al, 1986) has been documented in mice by Moore & Warren (1987), who also showed a synergy of this growth factor with interleukin-1, and in monkeys by Welte et al (1987). Granulocyte-macrophage colonystimulating factor has been shown to stimulate haemopoiesis in vivo both in animals (Donahue et al, 1986) and in patients (Groopman et al, 1987;Vadhan-Raj, et al, 1987).…”