Yu, J. et al. Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood 113, 3875-3884

Immunology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Blood (Impact Factor: 10.45). 02/2009; 113(16):3875-84. DOI: 10.1182/blood-2008-09-177055
Source: PubMed


Alloreactive natural killer (NK) cells are an important influence on hematopoietic stem cell transplantation (HSCT) outcome. In HLA-mismatched HSCT, alloreactivity occurs when licensed donor NK cells expressing inhibitory killer Ig-like receptors (KIR) for donor MHC class I ligands recognize the lack of the class I ligands in the mismatched recipient ("missing self"). Studies in HLA-matched HSCT, however, have also demonstrated improved outcome in patients lacking class I ligands for donor inhibitory KIR ("missing ligand"), indicating that classically nonlicensed donor NK cells expressing KIR for non-self MHC class I ligands may exhibit functional competence in HSCT. We examined NK function in 16 recipients of T cell-depleted allografts from HLA-identical or KIR-ligand matched donors after myeloablative therapy. After HSCT, nonlicensed NK cells expressing inhibitory KIR for non-self class I exhibit robust intracellular IFN-gamma and cytotoxic response to target cells lacking cognate ligand, gradually becoming tolerized to self by day 100. These findings could not be correlated with cytokine environment or phenotypic markers of NK development, nor could they be attributed to non-KIR receptors such as CD94/NKG2A. These findings confirm that NK alloreactivity can occur in HLA-matched HSCT, where tolerance to self is either acquired by the stem cell-derived NK cell after exiting the bone marrow or where tolerance to self can be temporarily overcome.

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    • "Following the identification of beneficial NK effects in the HLA-matched setting, the function of classically non-licensed NK cells has been directly explored in the context of post-transplantation reconstitution. In T-cell-depleted grafts from HLA-identical siblings, NK cells expressing KIR for non-self-HLA display strong IFNγ production and cytotoxicity to target stimulation during the first trimester post-transplantation (101). These findings have not been confirmed in a cohort of recipients of T cell-replete grafts from HLA-identical siblings. "
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    ABSTRACT: Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells are widely recognized as potent anti-leukemia mediators. Alloreactive donor NK cells have been shown to improve the outcome of allogeneic stem-cell transplantation for leukemia. In addition, in vivo transfer of NK cells may soon reveal an important therapeutic tool for leukemia, if tolerance to NK-mediated anti-leukemia effects is overcome. This will require, at a minimum, the ex vivo generation of a clinically safe NK cell product containing adequate numbers of NK cells with robust anti-leukemia potential. Ideally, ex vivo generated NK cells should also have similar anti-leukemia potential in different patients, and be easy to obtain for convenient clinical scale-up. Moreover, optimal clinical protocols for NK therapy in leukemia and other cancers are still lacking. These and other issues are being currently addressed by multiple research groups. This review will first describe current laboratory NK cell expansion and differentiation techniques by separately addressing different NK cell sources. Subsequently, it will address the mechanisms known to be responsible for NK cell alloreactivity, as well as their clinical impact in the hematopoietic stem cells transplantation setting. Finally, it will briefly provide insight on past NK-based clinical trials.
    Full-text · Article · Mar 2014 · Frontiers in Immunology
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    • "In this regard, it could be shown that NK cells can be aberrantly activated after transplantation and achieve effector function and functional competence in spite of lacking class I ligand for donor inhibitory KIR (Hsu et al., 2005, 2006; Clausen et al., 2007; Miller et al., 2007; Yu et al., 2009). Moreover, Yu et al. (2009) revealed that in HSCT settings " unlicensed " NK cells with inhibitory KIR for non-self-HLA are functional while " licensed " NK cells with inhibitory KIR for self-HLA appeared to be hyperresponsive . These findings were opposed by Bjorklund et al. (2010) who demonstrated that NK cells without self-HLA receptors remained hyporesponsive after HSCT thus remaining tolerant. "
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    ABSTRACT: The antileukemic potential of natural killer (NK) cells has been of rising interest in recent years. Interactions between inhibitory killer cell immunoglobulin-like receptors (KIR) and HLA class I ligands seem to be critically involved in the immunosurveillance process. It is also well established that mismatching of HLA class I-encoded KIR ligands in the setting of hematopoietic stem cell transplantation leads to allorecognition of leukemic cells by NK cells, which is in line with the concept of missing-self recognition. Recent data now suggest that KIR gene polymorphism constitutes another important parameter that needs to be taken into account for selection of suitable stem cell donors. Moreover, the role of KIR gene polymorphism for predisposition to leukemia is a current matter of debate. Here, we would like to review the role of KIR function and genetic polymorphism for recognition of leukemia and discuss the impact of these findings for developing novel concepts for NK cell-based immunotherapy strategies.
    Full-text · Article · Feb 2013 · Frontiers in Immunology
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    • "As KIR and HLA segregate independently, receptor-ligand mismatch between the graft's NK cells and the patient's cancer cells may exist in HLA-identical sibling donor or autologous HSCT. Although the receptor-ligand mismatched NK cells should be hyporesponsive in steady state against cancer cells without the cognate ligand, NK clones obtained from healthy individuals and from these patients have clearly been shown to be able to lyse target cells following the rule of normal receptor-ligand interactions (Grau et al, 2004; Yu et al, 2009). "
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    ABSTRACT: Analogous to T cells, Natural Killer (NK) cells may facilitate engraftment, combat infection, and control cancer in bone marrow or haematopoietic stem cell transplantation (HSCT); however, NK cells do not cause graft-versus-host disease. Killer immunoglobulin-like receptors (KIRs) regulate NK cell function, and recent data suggest that KIR is as important as its ligand (human leucocyte antigen; HLA) in HSCT for both malignant and non-malignant conditions. Because there is substantial variability in KIR gene content, allelic polymorphism, and cell-surface expression among people, careful selection of donors based on HLA and KIR is essential to optimize HSCT outcomes. Furthermore, NK cells may be used for adoptive immunotherapy after HSCT in place of conventional donor lymphocyte infusion, as part of pre-transplant cytoreductive therapy, or as an independent therapeutic agent in high-risk leukaemia in place of sibling donor HSCT.
    Full-text · Article · Aug 2011 · British Journal of Haematology
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