Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive immunotherapy using natural killer (NK) cells is currently under investigation, especially in situations where anti-neoplastic effect is needed but infusion of T cells is considered hazardous, such as in recipients of haematopoietic stem-cell transplantation (HSCT) from haploidentical donors. NK-cell therapy is mainly but not exclusively investigated in the setting of allogeneic stem-cell transplantation. NK cells may induce potent anti-leukaemic and possibly anti-rejection activity, and may even mitigate graft-versus-host disease (GvHD). It remains to be determined whether such effects are clinically important and whether or not they are mediated mainly or exclusively by KIR-HLA class I interactions. Recent advances in graft engineering has provided methods for isolating large numbers of purified NK cells. Several groups have shown that clinical-grade NK cells at doses up to 10(7)/kg may be collected and purified for the purpose of infusion to patients. Early results in a limited number of patients show that these cell doses may be administered without adverse events and possibly without inducing GvHD. Further study is required to determine whether such infusions will be useful in preventing graft rejection, exerting graft-versus-leukaemia effects, and/or hastening immune recovery.
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PMID:Natural-killer-cell-based treatment in haematopoietic stem-cell transplantation. 1699 85

Consideration of potential donors for transplantation includes a rigorous assessment of the availability and HLA-match status of family members, and the identification of suitable unrelated donors when related donors are not available. Because HLA gene products provoke host-versus-graft and graft-versus-host alloimmune responses, HLA matching serves a critical preventive role in lowering risks of graft failure and graft-versus-host disease (GVHD). At the same time, graft-versus-leukemia effects associated with HLA mismatching may provide an immunological means to lower the recurrence of post-transplant disease in high-risk patients. The definition of a suitable allogeneic donor is ever changing, shaped not only by current typing technology for the known HLA genes but also by the specific transplant procedure. Increased safety of alternative donor hematopoietic cell transplantation (HCT) has been achieved in part through advances in the field of immunogenetics. Increased availability of HCT 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 NK-KIR genes in transplantation.
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PMID:Risk assessment in haematopoietic stem cell transplantation: histocompatibility. 1744 54

Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56(+)CD16(+)KIR(+) NK cells and a reciprocal increase in CD56(+)CD16(-)KIR(-) cells. These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca(2+) oscillations, nuclear factor of activated T cells (NFAT) dephosphorylation, and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji, and KIR ligand-expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA-treated NK cells showed more IFN-gamma-producing cells. Using in vitro NK-cell differentiation, progenitor cells gave rise to more CD56(+)KIR(-) NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK-cell function and phenotype, which may have important implications for graft-versus-leukemia effects.
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PMID:The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations. 1749 33

This review focuses on recent research demonstrating the role alloreactive natural killer (NK) cells play in adoptive immunotherapy of leukemia in allogeneic hematopoietic transplantation. For patients with hematologic malignancies and an indication to allogeneic hematopoietic transplantation who do not have a matched sibling donor, unrelated donor, or cord blood transplants are almost always available (as long as the patient's ethnicity is represented in the donor registries). However, up to one half of patients relapse and do not make it to transplant during the time required for the donor search, completion of donor HLA typing, bone marrow harvest, and shipment. Donor-versus-recipient NK cell alloreactivity is effected by a functional repertoire of NK cells which express inhibitory Killer-Cell Immunoglobulin-like Receptor(s) (KIR) for self class I ligand(s), sense missing expression of donor KIR ligand(s) in the recipient and mediate alloreactions. It improves outcomes of HLA haplotype-mismatched ('haploidentical') transplants by controlling acute myeloid leukemia relapse without causing graft-versus-host disease. It is hoped the dramatic improvements afforded by the discovery of the role of NK cell alloreactivity will extend the use of haploidentical transplants, as the donors are, unlike the unrelated, immediately available family members.
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PMID:Role of KIRs and KIR ligands in hematopoietic transplantation. 1867 45

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)-like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1(+) NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3(+) NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3(+) (or by NKG2A(+)) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.
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PMID:Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. 1894 67

The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self-major histocompatibility complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2(-/-)gamma c(-/-) mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor alpha (IL-15R alpha) significantly augmented human NK cells. IL-15-IL-15R alpha complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16(+)KIR(+) NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56(hi)CD16(-)KIR(-) to CD56(lo)CD16(+)KIR(-), and finally to CD56(lo)CD16(+)KIR(+). These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15-responsive cells during immunotherapy strategies.
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PMID:IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. 1910 77

T-cell-depleted hematopoietic stem cell (HSC) transplantation from an HLA-haploidentical relative (Haplo HSCT) may represent a suitable and effective transplant option, as it is capable of rescuing not only adult patients with high-risk acute myeloid leukemias (AML) but also children with relapsed acute lymphoblastic leukemia (ALL), as shown by the two representative cases presented in this study. In Haplo HSCT, the anti-leukemia effect is mediated by "alloreactive" (i.e. KIR/HLA-mismatched) NK cells originated from donor HSCs. The availability of suitable KIR-specific monoclonal antibodies allows the prompt identification of alloreactive NK cell subsets as well as their quantification. This is important for selection of the most suitable donor and evaluation of the generation and persistence of these alloreactive NK cells after transplantation. In view of the favorable clinical outcome of children with chemo-resistant ALL, Haplo HSCT from an NK-alloreactive relative could become a first option in these high-risk leukemia patients.
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PMID:Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. 1948 79

The concept of tumor immunosurveillance has raised prospects for natural killer cell-based immunotherapy of human cancer. The cure of acute myeloid leukemia may depend on eradication of leukemic stem cells, the self-renewing component of leukemia. Whether natural killer cells can recognize and lyse leukemic stem cells is not known. To develop strategies that effectively target acute myeloid leukemia-leukemic stem cells, we investigated anti-leukemic effects of human alloreactive single KIR(+) natural killer cells. Natural killer effectors with KIR specificity mismatched with respect to HLA class I allotype of target cells effectively recognized acute myeloid leukemia-leukemic stem cells defined phenotypically as CD34(+)CD38(-), while healthy bone marrow-derived CD34(+)CD38(-) hematopoietic stem cells were spared, as demonstrated by cytotoxicity and hematopoietic colony-forming assays. The HDAC inhibitor valproic acid increased the activating NKG2D ligand-dependent lysis of acute myeloid leukemia-CD34(+)CD38(-) leukemic stem cells. These results show that alloreactive natural killer cells have the potential to detect and target leukemic stem cells, and thus to improve the treatment outcome in acute myeloid leukemia.
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PMID:Human acute myeloid leukemia CD34+CD38- stem cells are susceptible to allorecognition and lysis by single KIR-expressing natural killer cells. 1960 75

A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo-HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high-risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)-like receptors (KIR) and CD94/NKG2A, play a major role in the anti-leukaemia effect (mediating either inhibitory or activating signals). Haplo- HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell-depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include 'alloreactive' NK cells that kill leukaemic cells and prevent graft-versus-host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor-derived alloreactive NK cells in a cohort of paediatric patients given haplo-HSCT to cure acute, high-risk leukaemias.
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PMID:Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias. 1966 39

Donor-versus-recipient natural killer (NK) cell alloreactivity has been established as a key therapeutic element in HLA haplotype mismatched hematopoietic transplants in adult AML and pediatric ALL and as a possible beneficial effector in cord blood transplant for AML. It is effected by functional NK cells which express inhibitory killer cell immunoglobulin-like receptor(s) (KIR) for self-class I ligand(s), sense missing expression of donor KIR ligand(s) in the recipient and mediate alloreactions. At present NK cell allotherapy for leukemia is deployed through stem cell transplantation (and ensuing NK cell reconstitution) across KIR ligand mismatches. Studies have been performed to infuse NK cells for immunotherapy outside the fields of transplantation and/or harness the function of endogenous NK cells in patients with hematological malignancies.
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PMID:Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. 1971 93


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