Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia

Cooley, Sarah; Trachtenberg, Elizabeth; Bergemann, Tracy L.; Saeteurn, Koy; Klein, John P.; Le, Chap T.; Marsh, Steven G.E.; Guethlein, Lisbeth A.; Parham, Peter; Miller, Jeffrey S.; Weisdorf, Daniel J.

doi:10.1182/blood-2008-07-171926

Cited by 407 publications

(376 citation statements)

References 34 publications

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“…This allowed both gene copy number and haplotype assignment to the cohort 25. Briefly KIR haplotypes can be categorized as centromeric and telomeric A and B haplotypes according to the classification of Cooley et al 30 As individual KIR genes are in strong linkage disequilibrium with each other, these haplotypes may be more strongly associated with disease outcome than individual genes. We had complete data on 91 patients with HCV genotype 1 infection and 94 with HCV genotype 2 or 3 infection who had undergone treatment with pegylated IFN/ribavirin dual therapy.…”

Section: Resultsmentioning

confidence: 99%

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

et al. 2015

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Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)‐λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA‐C1C1 (P = 0.027), IFN‐λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA‐B (TapG:HLA‐B114D) (P = 0.007) and HLA‐DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN‐λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA‐C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non‐interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.

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Section: Resultsmentioning

confidence: 99%

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

et al. 2015

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“…One possible explanation is that T-cell depletion in these patients was partial, as administration of antithymocyte globulin in vivo only achieved a 2-3 log depletion, compared with the more extensive (4-5 log) in vitro T-cell depletion in haplotype-mismatched transplantations. Cooley 25 has reported that donor B/x, which mainly consisted of activating KIRs, reduced post transplant relapse and improved relapse-free survival in patients with AML. 25 Conversely, in our study, A/A, not B/x, and a low number of donor-activating KIR genes conferred a decreased relapse risk.…”

Section: Discussionmentioning

confidence: 99%

“…These KIR haplotypes also affect the clinical outcomes of HSCT, but the impacts are variedly or sometimes inconsistently reported. 18,24,25 On the basis of the above controversy and discrepancy, the present study investigated a panel of 116 patients at our center with different hematological malignancies and the effect of KIR genes and missing KIR ligands on the clinical outcome of URD-HSCT.…”

Section: Introductionmentioning

confidence: 99%

The beneficial impact of missing KIR ligands and absence of donor KIR2DS3 gene on outcome following unrelated hematopoietic SCT for myeloid leukemia in the Chinese population

Zhao

Lai

et al. 2010

Bone Marrow Transplant

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The effect of natural killer (NK) cell alloreactivity on the outcome of unrelated hematopoietic SCT (HSCT) remains a topic of debate. NK cell alloreactivity after allogeneic HSCT is regulated by killer-cell Ig-like receptors (KIRs). To investigate the influence of KIRs on outcome after unrelated HSCT, we retrospectively analyzed the HLA and KIR genotypes of 116 donorrecipient pairs. We found that missing KIR ligands in recipients were significantly associated with a decreased leukemic relapse risk (P ¼ 0.019, HR ¼ 0.329), mainly in myeloid disease (P ¼ 0.003, HR ¼ 0.193). This beneficial effect was seen in AML/myelodysplastic syndrome and also in chronic myeloid leukemia. In myeloid disease, missing KIR ligands also improved 5-year OS (P ¼ 0.034, HR ¼ 0.430) and disease-free survival (DFS) (P ¼ 0.024, HR ¼ 0.445). Meanwhile, the presence of donor-activating KIR2DS3 gene was associated with increased relapse risk (P ¼ 0.003, HR ¼ 5.046), decreased OS (P ¼ 0.004, HR ¼ 3.181) and DFS (P ¼ 0.003, HR ¼ 2.919) in myeloid disease. No effect was seen in patients with lymphoid disease. Our study indicated that, in unrelated HSCT for myeloid leukemia, missing KIR ligands in recipients offered a lower relapse risk and a long-term survival advantage. The presence of KIR2DS3 in the donor was an important risk factor for myeloid leukemia.

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“…Since both the HLA system and the KIR gene complex are characterized by variation in locus content, and segregate independent of each other, the potential array of interactions can vary considerably between individuals. Understanding the evolution and complexity of these receptor systems has broad medical relevance, since particular combinations of KIR and HLA alleles are associated with the outcome of viral infection, relapse of leukemia after transplantation, susceptibility to autoimmune disease, and successful pregnancy [7][8][9][10]. Because of its close evolutionary relationship to humans, and evidenced by similar immunological responses, the rhesus macaque (Macaca mulatta) is an important animal model to study the onset, progression, and outcome of infectious diseases, experimentally induced autoimmunity, and transplantation [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

et al. 2011

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NK cells are essential in shaping immune responses and play an important role during pregnancy and in controlling infections. Killer cell immunoglobulin-like receptors (KIRs) educate the NK cell and determine its state of activation. Our goal was to determine how the KIR repertoire of the rhesus macaque (Macaca mulatta) has been shaped during evolution. The presence or absence of 22 KIR gene groups was determined in 378 animals. Some unexpected observations were made in an outbred colony comprising animals of different origins. For instance, the KIR region appears to be highly plastic, and an unprecedented number of genotypes and haplotypes was observed. In contrast to humans, there is no distinction between group A and B haplotypes in the rhesus macaque, suggesting that different selective forces may be operative. Moreover, specific genes appear to be either present or absent in animals of different geographic origins. This extreme plasticity may have been propelled by co-evolution with the rhesus macaque MHC class I region, which shows signatures of expansion. The mosaic-like complexity of KIR genotypes as observed at the population level may represent an effective strategy for surviving epidemic infections. [3] but they are also involved with the vascularisation process during placentation, and thus contribute to reproductive success [4]. The education and activation state of the NK-cell is determined by the interactions of its receptors with their cognate ligands [5]. It is the shift in equilibrium of inhibitory and activating receptor signaling that ultimately leads to NK-cell activation in the form of cytokine production, cytotoxicity, or priming of the adaptive immune system [6].Killer cell immunoglobulin-like receptors (KIRs) may influence this balance through interactions with their ligands, the MHC molecules, which are called human leukocyte antigens 2719(HLA) in humans. Since both the HLA system and the KIR gene complex are characterized by variation in locus content, and segregate independent of each other, the potential array of interactions can vary considerably between individuals. Understanding the evolution and complexity of these receptor systems has broad medical relevance, since particular combinations of KIR and HLA alleles are associated with the outcome of viral infection, relapse of leukemia after transplantation, susceptibility to autoimmune disease, and successful pregnancy [7][8][9][10]. Because of its close evolutionary relationship to humans, and evidenced by similar immunological responses, the rhesus macaque (Macaca mulatta) is an important animal model to study the onset, progression, and outcome of infectious diseases, experimentally induced autoimmunity, and transplantation [11][12][13]. Moreover, certain human pathogens or their simiantrophic family members have adapted to primates as their natural host, and may show a host-specific pathology. Since in an experimental setting the onset of disease or the actual challenge with a pathogen can be controlled, it is possible to stu...

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Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia

Cited by 407 publications

References 34 publications

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

The beneficial impact of missing KIR ligands and absence of donor KIR2DS3 gene on outcome following unrelated hematopoietic SCT for myeloid leukemia in the Chinese population

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

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