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

Killer cell inhibitory receptors (KIR) are members of the immunoglobulin superfamily (Ig-SF) and transmembrane molecules type I expressed on human natural killer cells and some T lymphocytes. They are ligands for HLA class I antigens. According to the "missing-self" hypothesis, KIR deliver inhibitory signals that prevent target-cell lysis upon binding to the self MHC class I antigens. KIR regulates NK cell function concerned with the control graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (HSCT). The KIR repertoire is substantially influenced by the polymorphic and polygeneic nature of the KIR gene family, and there exist the polymorphism of KIR ligands mainly HLA-C molecule. So it is difficult to achieve the beneficial effect of NK cells on the outcome of partly HLA-mismatched hematopoietic cell transplantation. This review aims to provide background and previous observations on the KIRs which are thought to influence the outcome of HSCT.
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PMID:Killer cell inhibitory receptors involved in graft-versus-host disease and graft-versus-leukemia effect in allogeneic hematopoietic stem cell transplantation - review. 1515 42

Several leukaemia-specific antigens have been discovered in the recent past, which raised the possibility for T-cell-based immunotherapy for leukaemia. However, failure of such approaches involving interleukin-2 and/or T-cell-based immunotherapy indicated the importance of investigation of the human leucocyte antigen (HLA) status of the haematopoietic malignant cells. Considerable number of reports indicate that both HLA class I and class II are down-regulated in different cases of leukaemias, enabling them to evade immuno-surveillance. However, locus-specific down-regulation in leukaemia has not been widely investigated, although majority of cytotoxic T lymphocyte (CTL) responses are modulated by HLA-A and HLA-B, whereas expression of only HLA-C is unable to block natural killer (NK)-cell-mediated cytotolysis. Therefore, using RT-PCR, we have investigated the HLA class I transcriptional expression in a locus-specific manner, along with HLA-associated accessory molecules beta2-microglobulin and transporter-associated antigen processing molecule (TAP1). Our data suggest that in several newly diagnosed untreated leukaemic patients, HLA-C and beta2-microglobulin are expressed, but not the locus HLA-A or -B. Moreover, TAP1 and beta2-microglobulin were observed to be down-regulated in a number of cases of leukaemia. Our flow cytometric analysis of HLA-ABC also indicates a decrease in mean fluorescent intensity but no complete loss in surface expression of HLA class Ia on the leukaemic cells. Therefore, the observed low surface expression of HLA-ABC may be due to the down-regulation of transcription of HLA-A or -B itself and/or transcriptional suppression of the accessory molecules.
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PMID:Analysis of HLA class Ia transcripts in human leukaemias. 1613 50

This report describes the HLA-A*29 allele (A*2910) that has been identified by sequence-based typing in an 8-year-old Turkish female with leukaemia during search for a family-related stem cell donor. The allele is characterized by a nucleotide substitution (Guanine to Adenine) in exon 3 at position 258, leading to an amino acid exchange from glutamic acid to lysine at position 177. From family analysis and sequence comparison, the HLA-A*2910 allele has arisen from intergenic recombination with HLA-C. Structurally, the amino acid exchange at position 177 is probably functionally inactive due to the location of this amino acid exchange in the loop connecting the alpha(2) and alpha(3) domains.
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PMID:Intergenic recombination with HLA-C leads to a novel HLA-A*19 allele, HLA-A*2910, that is characterized by a functionally inactive amino acid exchange in the loop connecting the alpha and alpha domains. 1645 Dec 7

Recurrent malignancy remains a significant complication after allogeneic hematopoietic cell transplantation (HCT). Efforts to decrease relapse have included donor lymphocyte infusion to stimulate donor anti-recipient T-cell allorecognition of major and minor histocompatibility differences. Recently, alloreactive effects of donor natural killer cell-mediated inhibitory killer immunoglobulin-like receptor (KIR) recognition of recipient HLA-C and -B ligands have been described. We examined KIR ligand effects on risk of relapse in 1770 patients undergoing myeloablative T-replete HCT from HLA-matched or -mismatched unrelated donors for the treatment of myeloid and lymphoid leukemias. KIR ligands defined by HLA-B and -C genotypes were used to determine donor-recipient ligand incompatibility or recipient lack of KIR ligand. Among HLA-mismatched transplantations, recipient homozygosity for HLA-B or -C KIR epitopes predicted lack of KIR ligand and was associated with a decreased hazard of relapse (hazard ratio, 0.61; 95% confidence interval, .043-0.85; P = .004). Absence of HLA-C group 2 or HLA-Bw4 KIR ligands was associated with lower hazards of relapse (hazard ratio, 0.47; 95% confidence interval, 0.28-0.79, P = .004; hazard ratio, 0.56; 95% confidence interval, 0.33-0.97; P = .04, respectively). The decrease in hazard of relapse in patients with acute myelogenous leukemia was similar to that in patients with chronic myelogenous leukemia and acute lymphoblastic leukemia (P = .95). Recipient homozygosity for HLA-B or -C epitopes that define KIR ligands is likely to be a predictive factor for leukemia relapse after myeloablative HCT from HLA-mismatched unrelated donors. This effect was not observed in HLA-identical unrelated transplants.
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PMID:KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. 1686 53

Matching for HLA class I alleles, including HLA-C, is an important criterion for outcome of unrelated donor transplantation. However, haplotype-mismatched transplantations for myeloid malignancies, mismatched for killer immunoglobulin-like receptor (KIR) ligands in the graft-versus-host (GVH) direction, is associated with lower rates of graft-versus-host disease (GVHD), relapse, and mortality. This study investigated the effect of KIR ligand mismatching on the outcome of unrelated donor transplantation. The outcomes after 1571 unrelated donor transplantations for myeloid malignancies where donor-recipient pairs were HLA-A, -B, -C, and -DRB1 matched (n = 1004), GVH KIR ligand-mismatched (n = 137), host-versus-graft (HVG) KIR ligand-mismatched (n = 170), and HLA-B and/or -C-mismatched but KIR ligand-matched (n = 260) were compared using Cox regression models. Treatment-related mortality (TRM), treatment failure, and overall mortality were lowest after matched transplantations. Patients who received grafts from donors mismatched at the KIR ligand in the GVH or HVG direction and mismatched at HLA-B and/or C but matched at the KIR ligand had similar rates of TRM, treatment failure, and overall mortality. There were no differences in leukemia recurrence between the 4 groups. These results do not support the choice of an unrelated donor on the basis of KIR ligand mismatch determined from HLA typing.
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PMID:The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. 1686 58

Human NK cell function is regulated by clonally distributed inhibitory receptors termed "Killer cell Immunoglobulin-like Receptors" (KIRs) that recognize epitopes ("KIR ligands") shared by HLA-C and HLA-B class I allele groups and every functional NK cell in the repertoire expresses at least one receptor for self HLA-class I molecules. Consequently, when NK cells are confronted with allogeneic targets which do not express the inhibiting class I ligand(s) NK cell alloreactions may occur. Donor versus recipient NK alloreactions occur in full HLA haplotype-mismatched ("haploidentical") hematopoietic transplants that are KIR ligand mismatched in the Graft-versus-Host (GvH) direction. Variable frequencies of functional NK cells in the donor repertoire expressing a KIR for the HLA class I group which is absent in the recipient as their sole inhibitory receptor for self, sense the missing expression of the self class I ligand on allogeneic targets and mediate alloreactions ("missing self" recognition). In clinical trials, donor versus recipient NK alloreactions are highly beneficial as they reduce the risk of leukemia relapse, do not cause GvHD and markedly improve event-free survival.
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PMID:Natural killer cell recognition of missing self and haploidentical hematopoietic transplantation. 1691 11

T-cell large granular lymphocyte leukaemia (T-LGL) is a chronic clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGL presents with cytopenias, often accompanied by autoimmune diseases, suggesting clonal transformation arising from an initially polyclonal immune response. Various immunogenetic predisposition factors, previously described for both immune-mediated bone marrow failure and autoimmune conditions, may promote T-LGL evolution and/or development of cytopenias. The association of T-LGL was analysed with a number of immunogenetic factors in 66 patients, including human leucocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) genotype, KIR/KIR-L mismatch, CTLA-4 (+49 A/G),CD16-158V/F, CD45 polymorphisms, cytokine single nucleotide polymorphisms including: TNF-alpha (-308G/A), TGF-beta1 (codons 10 C/T, 25 G/C), IL-10 (-1082 G/A), IL-6 (-174 C/G), and IFN-gamma(+874 T/A). A statistically significant increase in A/A genotype for TNF-alpha-308, IL-10-1082, andCTLA-4 +49 was observed in T-LGL patients compared with control, suggesting that the G allele serves a protective role in each case. No association was found between specific KIR/HLA profile and disease. KIR/KIR-L analysis revealed significant mismatches between KIR3DL2 and KIR2DS1 and their ligands HLA-A3/11 and HLA-C group 2 (P = 0.03 and 0.01 respectively); the biological relevance of this finding is questionable. The significance of additional genetic polymorphisms and their clinical correlation to evolution of T-LGL requires future analysis.
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PMID:Immunogenetic factors determining the evolution of T-cell large granular lymphocyte leukaemia and associated cytopenias. 1715 96

NK cells are defined as those cells that lyse tumor cells without priming. In this study, we show that the preincubation of resting human NK cells with the leukemia cell CTV-1 primes NK cells to lyse NK-resistant cell lines, primary leukemias, and solid tumors even when HLA-matched, allogeneic or autologous. The primed NK cells remained nonresponsive to HLA-C matched and mismatched normal mononuclear cells from multiple donors. CD69, a known NK trigger receptor, was shown to be the predominant trigger on the tumor-primed NK cells because lysis was blocked with the rCD69 protein. The lack of lytic activity against normal hemopoietic cells implied that the ligand for CD69 is tumor restricted, and this was confirmed by experiments using fluorochrome labeled rCD69. It has been recently shown that resting NK cells require prior stimulation with IL-2 before triggering by all known NK-triggering ligands. In this study, we show that a tumor cell can provide the NK priming signal independently of IL-2. These data provide evidence for two NK evasion strategies for tumor cells, namely the prevention of priming (type1 evasion) and failure to trigger (type 2 evasion). Most NK-resistant cell lines are type 1 and fail to prime resting NK cells but are lysed by IL-2-primed NK cells. In contrast, CTV-1 cells prime resting NK cells but fail to trigger (type 2), and coincubation with CTV-1 primes for triggering by type 1 NK-resistant tumor cells. These tumor-activated NK cells lyse a broad spectrum of tumor cells with a degree of specificity never previously reported.
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PMID:Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. 1718 43

The responsible human leukocyte antigen (HLA) locus and the role of killer immunoglobulin-like receptor (KIR) ligand matching on transplantation outcome were simultaneously identified by multivariate analysis in 1790 patients with leukemia who underwent transplantation with T-cell-replete marrow from an unrelated donor (UR-BMT) through the Japan Marrow Donor Program. The graft-versus-leukemia (GVL) effect depended on leukemia cell type. HLA-C mismatch reduced the relapse rate in acute lymphoblastic leukemia (ALL) (hazard ratio [HR] = 0.47; P = .003), and HLA-DPB1 mismatch reduced it in chronic myeloid leukemia (CML) (HR = 0.35; P < .001). In contrast, KIR2DL ligand mismatch in the graft-versus-host (GVH) direction (KIR-L-MM-G) increased in ALL (HR = 2.55; P = .017). An increased rejection rate was observed in KIR2DL ligand mismatch in the host-versus-graft direction (HR = 4.39; P = .012). Acute GVH disease (GVHD) was increased not only in the mismatch of HLA-A, -B, -C, and -DPB1, but also in KIR-L-MM-G. As a whole, the mismatch of HLA-A, -B, and -DQB1 locus and KIR-L-MM-G resulted in increased mortality. In conclusion, not only the mismatch of HLA-C and -DPB1, but also KIR-L-MM-G affected leukemia relapse, which should be considered based on leukemia cell type. Furthermore, KIR-L-MM induced adverse effects on acute GVHD (aGVHD) and rejection, and brought no survival benefits to patients with T-cell-replete UR-BMT.
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PMID:Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. 1731 85

Recognition of recipient human leukocyte antigen (HLA) class I ligand by donor natural killer cell killer immunoglobulin-like receptors (KIR) has been proposed as the basis for donor allograft reactivity against malignancy leading to reduction in posttransplant relapse and higher survival for acute myelogenous leukemia. Analysis of KIR ligand effects in 1770 patients undergoing myeloablative T-replete hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors showed that lack of KIR ligand in patients for inhibitory KIR was associated with lower hazards of relapse in leukemia patients with in HLA-mismatched transplants [hazard ratio (HR): 0.061; 95% confidence interval (CI): 0.43-0.85; P-value = 0.004]. Absence of HLA-C group 2 or HLA-Bw4 KIR ligands were each associated with lower hazards of relapse (HR: 0.47; 95% CI: 0.28-0.79; P-value = 0.004; HR: 0.56; 95% CI: 0.33-0.97; P-value = 0.04, respectively). Based on these analyses, recipient homozygosity for HLA-B or -C epitopes that define KIR ligands is likely to be a predictive factor for leukemia relapse following myeloablative HCT from unrelated donors. KIR genotyping for unrelated donors and recipients will clarify the role of these receptors in transplant outcome.
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PMID:Hematopoietic stem cell transplantation: killer immunoglobulin-like receptor component. 1744 61


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