Interferon alpha in combination with GM-CSF induces the differentiation of leukaemic antigen-presenting cells that have the capacity to stimulate a specific anti-leukaemic cytotoxic T-cell response from patients with chronic myeloid leukaemia.
Although interferon alpha (IFN-alpha) is able to induce haematological remission in 60-80% of patients with chronic myeloid leukaemia (CML) in early chronic phase, major cytogenetic remissions are only achievable in 30-40%. Recent clinical data suggest that the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to IFN-alpha therapy can significantly improve the cytogenetic response in some patients, although the mechanism remains unknown. We hypothesized that the combination of GM-CSF and IFN-alpha induces the differentiation of dendritic cells, which subsequently stimulates a specific anti-leukaemic response. Monocytes from CML patients were cultured in GM-CSF and interleukin (IL)-4 (GM/IL-4)or in GM-CSF and IFN-alpha (GM/IFN-alpha). After 7 d, the number of cells exhibiting typical antigen-presenting cell (APC) morphology was equal in both groups, and fluorescence in situ hybridization (FISH) analysis confirmed that the APCs generated with GM/IFN-alpha were of leukaemic origin. Phenotypically, both sets of APCs expressed typical surface markers; however, CD86, CD83, CD11c, HLA-ABC and HLA-DR expression was significantly higher in the GM/IFN-alpha APCs, whereas CD1a expression was significantly lower. In mixed lymphocyte reactions (MLR), GM/IFN-alpha APCs stimulated the proliferation of allogeneic T cells significantly better than GM/IL-4 APCs. However, both groups of APCs stimulated autologous T-cell proliferation equally. Finally, we assessed the ability of GM/IFN-alpha APCs to induce a leukaemia-specific cytotoxic T-cell response. Some samples generated cytotoxic T lymphocytes (CTLs) that specifically lysed bcr-abl-positive target cells. These data show that the combination of GM-CSF and IFN-alpha, when used in vitro, induces the differentiation of malignant APCs with potent T-cell stimulatory capacity. Although there is no in vivo evidence to support these findings, it is possible that, when administered to CML patients, GM-CSF in combination with IFN-alpha results in the generation of highly stimulatory leukaemic APCs.
Chen
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Klinische Kooperationsgruppe Hämatopoetische Zelltransplantation, Medizinische Klinik III, Klinikum Grosshadern, Universität München and GSF (National Research Centre for Environment and Health), München, Germany.
Regn
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Raffegerst
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Kolb
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Roskrow
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D000938:Antigen-Presenting Cells / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016898:Interferon-alpha / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000032:analysis; D015847:Interleukin-4 / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology*; D008213:Lymphocyte Activation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016898:Interferon-alpha; D020382:Interleukin-18; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor