Monocyte‐mediated killing of human leukaemia is enhanced by administration of granulocyte‐macrophage colony stimulating factor following chemotherapy

Abstract

Summary.We studied the capacity of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) to modulate monocyte anti-leukaemic activity when administered to patients following myelosuppressive chemotherapy. The leukaemic cell lines K562, U937 and KG-1 were used as models of human leukaemia as they exhibit differential sensitivity to cell-mediated or TNF-mediated cytotoxicity. Monocyte tumouricidal activity was augmented by rhGM-CSF or lipopolysaccharide (LPS) alone in vitro against leukaemic blasts, whereas granulocyte-colony stimulating factor (rhG-CSF) was without effect. rhGM-CSF and LPS exhibited an additive effect in stimulating the cytotoxic effect of monocytes against K562 blasts compared with either agent alone (P < 0 . 001). Both cell-mediated and soluble TNF-mediated killing of leukaemic blasts was augmented by rhGM-CSF administration to patients following chemotherapy. This effect persisted for up to 4 weeks after cessation of GM-CSF therapy. The administration of rhGM-CSF significantly increased the anti-leukaemic activity of monocytes against leukaemic targets that were resistant to secreted TNF, probably via a transmembrane TNFdependent mechanism. Therapy with rhG-CSF exhibited a minimal effect. We conclude that administration of rhGM-CSF, but not rhG-CSF, augments the tumouricidal properties of the monocyte-macrophage system, particularly during recovery from myelosuppressive chemotherapy. Moreover, the killing mechanism is direct and not mediated by an antibody-dependent cellular cytotoxic (ADCC) mechanism. Killing of TNF-resistant leukaemic cells in particular may be augmented via cell-to-cell contact.

Monocyte Anergy in Septic Shock Is Associated with a Predilection to Apoptosis and Is Reversed by Granulocyte‐Macrophage Colony‐Stimulating Factor Ex Vivo

“…Granulocyte-macrophage colony-stimulating factor (GM-CSF) primes the antimicrobial activation of monocytes in vitro [34] and restores monocyte function when administered to patients after chemotherapy [35,36]. When administered to animals, GM-CSF was protective against supralethal doses of bacteria or Candida species [37], although when given after the onset of abdominal sepsis, GM-CSF did not confer benefit [38].…”

Granulocyte‐Macrophage Colony‐Stimulating Factor Augments Phagocytosis ofMycobacterium aviumComplex by Human Immunodeficiency Virus Type 1–Infected Monocytes/Macrophages In Vitro and In Vivo

“…Clinical improvement after GM-CSF therapy has similarly been reported in patients with advanced HIV infection and fluconazole-resistant C. albicans infection [13]; augmentation of other aspects of macrophage function has been found in other immunosuppressed patients [14]. Preliminary data from an ongoing study of AIDS patients receiving nucleoside therapy has shown that GM-CSF administrated twice weekly for 6 months not only reduced the frequency of opportunistic infections but also significantly decreased virus load and increased CD4 cell counts of those subjects [15].…”

Activation of peritoneal cells upon in vivo transfection with a recombinant alphavirus expressing GM-CSF

“…growing tumor. Despite the observed activation of peritoneal macrophages, only a slight delay in tumor growth was observed with a relatively low number of viral particles, ie 5 × 10 6 . It should, however, be noted that the tumor cells employed in these studies grow extremely fast upon i.p.…”

“…Then cells were incubated in 0.1% X-gal diluted in Hepes buffer (pH 8, 5 mm K 3 Fe(CN) 6 , 5 mm K 4 Fe(CN) 6 ț3H 2 O, 2 mm MgCl 2 ț6H 2 O). After incubation for 2 h, the staining reaction was stopped by removing the X-gal solution.…”

“…GM-CSF is a 18-30 kDa glycoprotein produced by T cells, monocytes and endothelial cells. It stimulates monocytes and macrophages to become tumoricidal both in vitro and in vivo [5][6][7][8][9] and induces macrophage recruitment. 10 As a tumor model we used murine ovarian tumor cells (MOT cells), a teratocarcinoma which arose spontaneously in female C3HeB/FeJ mice.…”