KIR Ligands and Prediction of Relapse after Unrelated Donor Hematopoietic Cell Transplantation for Hematologic Malignancy

Leiden University, Leyden, South Holland, Netherlands
Biology of Blood and Marrow Transplantation (Impact Factor: 3.4). 09/2006; 12(8):828-36. DOI: 10.1016/j.bbmt.2006.04.008
Source: PubMed


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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Available from: Jean-Denis D Bignon, Aug 24, 2015
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    • "However the precise role of KIR-ligand mismatch in HSCT is not known. In some patients treated with allogeneic-HSCT, PB-NK cell alloreactivity as determined by missing KIR ligands appears to predict reduced rates of relapse and graft versus host disease (GVHD) [8], [9]. Additionally, in MM patients undergoing matched allogeneic-HSCT, an activated donor KIR haplotype (Bx) has been associated with a significantly lower risk of relapse and better PFS [10]. "
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    ABSTRACT: Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "direction amongst patients subjected to HSCT for leukaemias [24]. Many other studies published since describe KIR gene associations with anti-tumour effects and post-transplant clinical endpoints [25] [26] [27] [28] [29] [30] [31]. Differences in patient demographics, clinical management, the preferred transplant modality and KIR "
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    ABSTRACT: a b s t r a c t Killer-cell immunoglobulin-like receptors (KIR) are membrane proteins expressed by natural killer cells and CD8 lymphocytes. The KIR system consists of 17 genes and 614 alleles, some of which bind human leukocyte antigens (HLA). Both KIR and HLA modulate susceptibility to haematological malignancies, viral infections and autoimmune diseases. Molecular epidemiology studies employ traditional statistical methods to identify links between KIR genes and disease. Here we describe our results at applying artificial intelligence algorithms (support vector machines) to identify associations between KIR genes and disease. We demonstrate that these algorithms are capable of classifying samples into healthy and diseased groups based solely on KIR genotype with potential use in clinical decision support systems.
    Full-text · Article · Sep 2013 · Computers in Biology and Medicine
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    • "According to this study, the risk of CMV reactivation following HLA-matched HSCT is associated with individual donor KIR genes, but only when their evolutionarily specific HLA-C ligand is absent from the shared donor/recipient genotype. Our results add to the evidence that non-licensed NK cells can play an important role in host control of tumors (Hsu et al., 2005, 2006; Clausen et al., 2007; Miller et al., 2007; Venstrom et al., 2009) and infection, specifically murine CMV (Orr et al., 2010), with one important difference. Unlike previous reports, our study suggests that “presumably non-licensed” NK cells (inhibitory KIRs with ligand absent-from-genotype) are associated with worse, not better, clinical outcome, while comparable activating KIRs (those with ligand absent-from-genotype) have qualitatively opposite effects, being associated with better, not worse, clinical outcome among our subjects. "
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    ABSTRACT: Natural killer (NK) cells whose killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen (HLA) ligand are "licensed" for activity. In contrast, non-licensed NK cells display KIRs for which ligand is absent from the self genotype and are usually hyporesponsive. Surprisingly, non-licensed cells are active in tumor control after hematopoietic stem-cell transplantation (HSCT) and dominate NK response to murine cytomegalovirus (CMV) infection. From those reports, we hypothesized that control of human CMV early after HSCT is influenced by donor KIR genes whose HLA ligand is absent-from-genotype of HLA-matched donor and recipient. To investigate, we studied CMV reactivation through Day 100 after grafts involving CMV-seropositive donor and/or recipient. A multivariate proportional rates model controlled for variability in surveillance and established covariates including acute graft-versus-host disease; statistical significance was adjusted for testing of multiple KIRs with identified HLA class I ligand (2DL1, 2DL2/3, 2DS1, 2DS2, full-length 2DS4, 3DL1/3DS1, 3DL2). Among HSCT recipients (n = 286), CMV reactivation-free survival time varied with individual donor KIR genes evolutionarily specific for HLA-C: when ligand was absent from the donor/recipient genotype, inhibitory KIRs 2DL2 (P < 0.0001) and 2DL1 (P = 0.015) each predicted inferior outcome, and activating KIRs 2DS2 (P < 0.0001), 2DS1 (P = 0.016), and 2DS4 (P = 0.016) each predicted superior outcome. Otherwise, with ligand present-in-genotype, donor KIR genes had no effect. In conclusion, early after HLA-matched HSCT, individual inhibitory and activating KIR genes have qualitatively different effects on risk of CMV reactivation; unexpectedly, absence of HLA-C ligand from the donor/recipient genotype constitutes an essential cofactor in these associations. Being KIR- and HLA-C-specific, these findings are independent of licensing via alternate NK cell receptors (NKG2A, NKG2C) that recognize HLA-E.
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