The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D-target-cell interactions.
To study natural killer (NK) cell-mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56(+) cells to inhibit granulocyte macrophage-colony-forming unit (CFU-GM) formation by leukemic CD34(+) cells. In 14 HLA-identical donor-recipient pairs, donor CD56(+) cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% +/- 9% vs 39.5% +/- 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56(+)CD3(-) (natural killer [NK]) and CD56(+)CD3(+)(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34(+) cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain-related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, in vivo, CML cells may avoid NK-cell-mediated immune destruction by immune escape, shedding MICA into the plasma, thereby down-regulating NKG2D on CML CD56(+) cells.
Sconocchia
Giuseppe
G
Stem Cell Allotransplantation Section, Hematology Branch, National Heart Lung and Blood Institute, Department of Transfusion Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Lau
Michelle
M
Provenzano
Maurizio
M
Rezvani
Katayoun
K
Wongsena
Wachanan
W
Fujiwara
Hiroshi
H
Hensel
Nancy
N
Melenhorst
Jos
J
Li
Jonming
J
Ferrone
Soldano
S
Barrett
A John
AJ
D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D016022:Case-Control Studies; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D005260:Female; D006680:HLA Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology*; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K; D014411:Neoplastic Stem Cells / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell