IntroductionImproved outcome of acute myeloid leukemia (AML) after stemcell transplantation across the human leukocyte antigen (HLA) class I barrier highlighted a potential of natural killer (NK) cells in recognition and elimination of residual malignant cells by the graft-versus-leukemia (GVL) effect in the absence of graft-versushost disease (GVHD). 1,2 NK cells develop rapidly from transplanted progenitor cells but display numerous phenotypic abnormalities and a functional immaturity, which may limit their effectiveness in tumor rejection in vivo. 3,4 Adoptive transfer of mature NK cells in the early posttransplantation period is therefore a rational approach aimed at providing the patient with the benefit of competent cytotoxic effectors. 5 NK cells are innate immunity CD56 ϩ CD3 Ϫ lymphocytes, the function of which is regulated by the integration of signals delivered from multiple inhibitory and activating receptors. 6 The killer immunoglobulin-like receptors (KIRs), which are clonally distributed in the NK-cell repertoire, recognize allelic groups of HLA class I molecules on target cells and are dominant determinants of NK-cell function. 7 NK cytotoxicity is inhibited on recognition of "self" HLA class I molecules, whereas absence or loss of HLA class I can render cells susceptible to NK-mediated lysis. In the transplant setting from haploidentical stem-cell donor, alloreactivity of NK cells is provided by the KIR-HLA class I mismatch. 8 In addition to sensing the missing self HLA class I molecules, NK cells need to be stimulated through engagement of activating NK receptors by specific cell-surface ligands expressed by target cells. 9,10 NKG2D is one of the best characterized receptors required for NK-mediated tumor immunosurveillance. 11 In mice, NKG2D function can protect the host from tumor initiation and also eradicate existing tumors expressing the H60 and Rae-1 ligands. 12,13 The human NKG2D ligands (NKG2D-L) include 2 families of proteins belonging to major histocompatibility complex class I (MIC)-related molecules, and UL-16 binding proteins (ULBP). 14,15 In epithelial tissue, the surface expression of NKG2D-L is up-regulated in response to cellular stress, including heat shock, DNA damage, and stalled DNA replication, which are common in human cancer. 16,17 A notion that NKG2D-L play a key role as tumor-associated ligands rendering cells susceptible to NK-mediated lysis, has encouraged pharmacologic approaches to achieve the NKG2D-L induction. 18,19 Understanding the molecular interactions regulating the NK function has uncovered numerous escape mechanisms preventing recognition of leukemic blasts by NK cells. Unlike in solid tumors, which frequently down-regulate HLA class I molecules, malignant leukemic cells carry high levels of HLA class I having a protective effect. 20 NKG2D-L are absent or expressed at low levels in the majority of patients with acute leukemia, 21-23 thereby preventing efficient activating interactions. An additional route of tumor The online version of this article contain...

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