MATURATION-DEPENDENT SUSCEPTIBILITY TO MONOCYTE-MEDIATED CYTOTOXICITYIN ACUTE MYELOID-LEUKEMIA

In view of cellular immunotherapy with cytotoxic monocytes in minimal residual leukemia we have studied the effects of monocytes on the grow th and survival of leukemic cells from cell lines and from patients wi th acute myeloid leukemia (AML). Using highly purified and interferon- gamma (IFN gamma) activated human monocytes, monocyte-mediated cytotox icity (MMC) was evaluated in an MTT-based colorimetric cytotoxicity as say against six human leukemic cell lines (U937, THP1, KG1, K562, HL60 , and 1,25(OH)(2)D-3 differentiated HL60 cells) and cells from AML pat ients. Leukemic cells from cell lines with an immature phenotype were found to be resistant to MMC, whereas leukemic cells with a more matur e and monocytic phenotype were sensitive. This paralleled the sensitiv ity to tumor necrosis factor-alpha. (TNF-alpha). AML cells from patien ts with an immature phenotype (FAB-M1/M5A) were significantly less sen sitive to MMC as compared to more mature AML cells (FAB-M2/M4/M5B). Th e growth stimulatory effects of non-activated monocytes on immature AM L cells could he abrogated in the presence of IFN gamma or IL-3 and GM -CSF. In addition, these cytokines further potentiated MMC, preferenti ally affecting cells with a more mature phenotype. AML cells with an i mmunologically immature phenotype (CD34(high), HLA-Dr(low), CD13(low), CD14(low)) were revealed as the least sensitive cells to MMC. The gro wth stimulatory effects of IL-3/GM-CSF with or without TNF-alpha on AM L cells correlated with resistance to MMC. In addition, the cytolytic effects of TNF-alpha in the presence of IFN gamma correlated with an i ncreased susceptibility of AML cells to MMC. In conclusion, our data s trongly indicate that MMC is related to maturation in AML, which is co rrelated to the differential stimulatory and cytolytic effects of mono cyte-derived cytokines such as IL-3, GM-CSF, and TNF-alpha.