title: Maturation-dependent susceptibility to monocyte-mediated cytotoxicity in acute myeloid leukemia.
abstract: In view of cellular immunotherapy with cytotoxic monocytes in minimal residual leukemia we have studied the effects of monocytes on the growth and survival of leukemic cells from cell lines and from patients with acute myeloid leukemia (AML). Using highly purified and interferon-gamma (IFN gamma) activated human monocytes, monocyte-mediated cytotoxicity (MMC) was evaluated in an MTT-based colorimetric cytotoxicity assay against six human leukemic cell lines (U937, THP1, KG1, K562, HL60, and 1,25(OH)2D3 differentiated HL60 cells) and cells from AML patients. Leukemic cells from cell lines with an immature phenotype were found to be resistant to MMC, whereas leukemic cells with a more mature and monocytic phenotype were sensitive. This paralleled the sensitivity to tumor necrosis factor-alpha (TNF-alpha). AML cells from patients with an immature phenotype (FAB-M1/M5A) were significantly less sensitive to MMC as compared to more mature AML cells (FAB-M2/M4/M5B). The growth stimulatory effects of non-activated monocytes on immature AML cells could be abrogated in the presence of IFN gamma or IL-3 and GM-CSF. In addition, these cytokines further potentiated MMC, preferentially affecting cells with a more mature phenotype. AML cells with an immunologically immature phenotype (CD34(high), HLA-Dr(low), CD13(low), CD14(low)) were revealed as the least sensitive cells to MMC. The growth stimulatory effects of IL-3/GM-CSF with or without TNF-alpha on AML cells correlated with resistance to MMC. In addition, the cytolytic effects of TNF-alpha in the presence of IFN gamma correlated with an increased susceptibility of AML cells to MMC. In conclusion, our data strongly indicate that MMC is related to maturation in AML, which is correlated to the differential stimulatory and cytolytic effects of monocyte-derived cytokines such as IL-3, GM-CSF, and TNF-alpha.
authors.affiliation: Department of Hematology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: van de Loosdrecht
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: R H
authors.initials: RH
authors.lastname: Beelen
authors.forename: M G
authors.initials: MG
authors.lastname: Broekhoven
authors.forename: M H
authors.initials: MH
authors.lastname: van Hooff
authors.forename: A M
authors.initials: AM
authors.lastname: Dräger
authors.forename: P C
authors.initials: PC
authors.lastname: Huijgens
authors.forename: M M
authors.initials: MM
authors.lastname: Langenhuijsen
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D002450:Cell Communication; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D011994:Recombinant Proteins