The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia

Cook, Mark; Milligan, Donald; Fegan, Christopher; Darbyshire, P. J.; Mahendra, Premini; Craddock, Charles; Moss, Paul; Briggs, David

doi:10.1182/blood-2003-02-0438

Cited by 171 publications

(161 citation statements)

References 37 publications

(45 reference statements)

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“…Whereas in one study, C2 ligands were associated with an increased relapse rate (22), in another study epistatic interaction between C2 in the recipient and the stimulatory KIR2DS2 in the donor was found (23). In the present study, no influence of C2 ligands on the relapse rate was found.…”

Section: Discussioncontrasting

confidence: 73%

Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor

Fischer

Ottinger

Ferenčík

et al. 2007

The Journal of Immunology

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Killer Ig-like receptors (KIR) and HLA class I ligands were studied in unrelated hemopoietic stem cell transplantation for chronic myeloid leukemia (n = 108). Significantly improved overall survival was observed in patients, which were homozygous for HLA-C-encoded group 1 (C1) ligands compared with those with group 2 (C2) ligands. Favorable outcome in the former patient group was an early effect that was highly significant in patients transplanted with G-CSF-mobilized peripheral blood and patients with advanced disease stages. In contrast, presence of C1 ligands in the donor was associated with significantly reduced patient survival. The differential roles of the two HLA-C ligands are explained in the context of a biased NK cell reconstitution, which is generally dominated by the presence of C1- but absence of C2-specific NK cells. The clinical observations are corroborated by in vitro experiments showing that NK cells derived from hemopoietic progenitor cells generally acquire the C1-specific inhibitory KIR2DL2/3 at earlier time points and with higher frequency than the C2-specific KIR2DL1. These findings define a novel determinant for understanding the role of NK cells in clinical hemopoietic stem cell transplantation.

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Section: Discussioncontrasting

confidence: 73%

Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor

Fischer

Ottinger

Ferenčík

et al. 2007

The Journal of Immunology

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“…13 Also, the analyses of the activating KIR receptors showed donors' KIR2DS2 to be a significant risk factor for overall survival (OS) of myeloid leukemia HLA-C2C2 patients. 14 In addition, not only individual genes but also KIR haplotypes of donors were associated with an increased risk of acute GVHD (aGVHD), higher relapse rates and worse OS of HLA-C1C1 patients diagnosed with myeloid diseases. 15 However, all described observations apply to distinct patient groups, and differ substantially depending on transplant protocols, as reviewed recently by Verheyden and Demanet.…”

Section: Introductionmentioning

confidence: 99%

KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation

Ludajic

Balavarca

Bickeböller

et al. 2009

Bone Marrow Transplant

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Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/ 12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II-IV) (hazard ratio (HR) ¼ 2.23, 95% confidence interval (95% CI): 1.21-4.10, P ¼ 0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR ¼ 2.37, 95% CI: 1.16-4.84, P ¼ 0.018) and in HLA-Bw4 À (HR ¼ 3.20, 95% CI: 1.35-7.60, P ¼ 0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II-IV) (HR ¼ 0.24, 95% CI: 0.07-0.85, P ¼ 0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands.

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“…12 Subsequently, a second model known as the receptorligand model (or missing ligand model) was proposed, in which the consideration is on the KIR genotype rather than the ligand of the donor's KIR and whether its corresponding ligand is missing in the recipient. There are several reports retrospectively analyzing transplant outcome on the basis of this model, with some showing an advantage in certain aspects, for example OS, 13,14 relapse-free survival and 13-15 TRM, 13,16 whereas others failed to find any beneficial effects. These discrepancies are probably linked to heterogeneous patient populations, differences in the sources of stem cells and various conditioning regimens.…”

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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The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia

Cited by 171 publications

References 37 publications

Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor

Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor

KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation

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

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