Alloreactive natural killer cells in hematopoietic stem cell transplantation

Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
Leukemia research (Impact Factor: 2.35). 01/2011; 35(1):14-21. DOI: 10.1016/j.leukres.2010.07.030
Source: PubMed


Allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia can play a major role in reducing the risk of relapse by inducing a graft versus leukemia (GVL) effect. Here, we review the effectiveness of mismatching inhibitory killer-cell-immunoglobulin-like receptors (KIR) on donor natural killer (NK) cells as a mechanism for GVL. We review the range of KIR and the importance of T cell and NK cell content of the graft, together with considerations of the graft source. Further understanding of conditioning and mechanisms to reduce graft versus host disease (GVHD) will improve our ability to manipulate NK cells in HSCT.

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    • "Collectively, it is clear that the exploitation of NK cell alloreactivity as a therapeutic advantage in HSCT is promising, and certain patients with myeloid malignancies have benefited from allogeneic HSCT. KIR genotyping of several best HLA-matched potential UDs may change clinical practice in the future [54]. "
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    ABSTRACT: The selection of hematopoietic stem cell transplantation (HSCT) donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA) match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR) genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.
    Full-text · Article · Oct 2012
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    • "Blocking Ly49 inhibitory receptors enhanced antitumor activity in vitro and in vivo111 and in human, antibodies blocking KIR are currently tested in a Phase II clinical trial.112 NK allogeneic recognition via their KIR repertoire has a major role in reducing the risk of relapse by inducing a graft versus leukemia effect after allogeneic hematopoietic stem cell transplantation.113 "
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    ABSTRACT: Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed.
    Full-text · Article · Apr 2012 · Biologics: Targets & Therapy
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    • "However, certain studies have either found no beneficial effect of KIR ligand mismatch or reported even worse outcomes following partially HLA mismatched stem cell transplantation [21], [22]. Moreover, other studies have proposed protective roles for NK cell recognition of allogenic HLA using activating KIR [23], [24] or they suggested a role for uneducated NK cells [25], [26], [27] (for review see [28], [29]). Some of these discrepancies may be due to distinct conditioning regimens, differences in the preparation, the source and the dose of the transplanted stem cells and/or the fact that the cohorts included patients with distinct hematological malignancies that are based on different primary genetic lesions. "
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    ABSTRACT: Natural Killer (NK) cells are thought to protect from residual leukemic cells in patients receiving stem cell transplantation. However, multiple retrospective analyses of patient data have yielded conflicting conclusions regarding a putative role of NK cells and the essential NK cell recognition events mediating a protective effect against leukemia. Further, a NK cell mediated protective effect against primary leukemia in vivo has not been shown directly. Here we addressed whether NK cells have the potential to control chronic myeloid leukemia (CML) arising based on the transplantation of BCR-ABL1 oncogene expressing primary bone marrow precursor cells into lethally irradiated recipient mice. These analyses identified missing-self recognition as the only NK cell-mediated recognition strategy, which is able to significantly protect from the development of CML disease in vivo. Our data provide a proof of principle that NK cells can control primary leukemic cells in vivo. Since the presence of NK cells reduced the abundance of leukemia propagating cancer stem cells, the data raise the possibility that NK cell recognition has the potential to cure CML, which may be difficult using small molecule BCR-ABL1 inhibitors. Finally, our findings validate approaches to treat leukemia using antibody-based blockade of self-specific inhibitory MHC class I receptors.
    Preview · Article · Nov 2011 · PLoS ONE
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