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      Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies


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          Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies.

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          HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

          The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
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            In search of the ‘missing self’: MHC molecules and NK cell recognition

            Immunology Today, 11, 237-244
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              Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.

              Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.

                Author and article information

                URI : http://frontiersin.org/people/u/115902
                URI : http://frontiersin.org/people/u/232674
                URI : http://frontiersin.org/people/u/233371
                URI : http://frontiersin.org/people/u/230278
                URI : http://frontiersin.org/people/u/185663
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                13 May 2015
                : 6
                [1] 1Department of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation , Doha, Qatar
                [2] 2Deep Immunophenotyping Core, Division of Translational Medicine, Sidra Medical and Research Center , Doha, Qatar
                [3] 3Clinical Research Center, Division of Translational Medicine, Sidra Medical and Research Center , Doha, Qatar
                Author notes

                Edited by: Raquel Tarazona, University of Extremadura, Spain

                Reviewed by: Roberto Biassoni, Istituto Giannina Gaslini, Italy; Björn Önfelt, Karolinska Institutet, Sweden

                *Correspondence: Gianfranco Pittari, Department of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar, gpittari@ 123456hamad.qa ; Sergio Rutella, Clinical Research Center, Division of Translational Medicine, Sidra Medical and Research Center, P. O. Box 26999, Doha, Qatar, srutella@ 123456sidra.org

                Specialty section: This article was submitted to NK Cell Biology, a section of the journal Frontiers in Immunology

                Copyright © 2015 Pittari, Filippini, Gentilcore, Grivel and Rutella.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 175, Pages: 22, Words: 19786

                natural killer cell,cytokine-induced killer cell,interleukin-2,interleukin-15,good manufacturing practice,leukemia,immunotherapy


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