Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation

Sekine, Takuya; Marín, David; Cao, Kai; Li, Li; Mehta, Pramod P.; Shaim, Hila; Sobieski, Catherine; Jones, Roy B.; Oran, Betül; Hosing, Chitra; Rondón, Gabriela; Alsuliman, Abdullah; Paust, Silke; Andersson, Börje S.; Popat, Uday; Kebriaei, Partow; Müftüoğlu, Muharrem; Basar, Rafet; Kondo, Kimie; Nieto, Yago; Shah, Nina; Olson, Amanda; Alousi, Amin M.; Liu, Enli; Sarvaria, Anushruti; Parmar, Simrit; Armstrong‐James, Darius; Imahashi, Nobuhiko; Molldrem, Jeffrey J.; Champlin, Richard E.; Shpall, Elizabeth J.; Rezvani, Katayoun

doi:10.1182/blood-2016-03-706317

Cited by 58 publications

(50 citation statements)

References 41 publications

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“…Empirical data on the NK cell education process following transplantation remain controversial. In the setting of CBT, Sekine et al (2016) reported that HLA-C1/x patients should receive an HLA-C1-KIR2DL2/L3/S2 cord blood graft, while HLA-C2/C2 patients may benefit from an HLA-C2-KIR2DL1/S1 graft. However, Sungur et al (2013) have indicated that NK cell licensing corresponds with the donor and not the host MHC haplotype following mismatched allo-HSCT in mice.…”

Section: Discussionmentioning

confidence: 99%

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Zhao

Luo

et al. 2017

Br J Haematol

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Licensed natural killer (NK) cells have been demonstrated to have anti-cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor-recipient pairs and the killer cell immunoglobulin-like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post-T-cell-replete haploidentical stem cell transplantation. Multivariate analysis showed that donor-recipient KIR ligand graft-versus-host or host-versus-graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377-4·744, P = 0·003) post-transplantation. Donor-recipient KIR ligand matching decreased CMV reactivation [51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012], refractory CMV infection [17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004] and CMV disease [3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024] by day 100 post-transplantation. In addition, the percentage of γ-interferon expression on donor-derived NK cells was significantly higher in the recipients among the recipient-donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft-versus-host or host-versus-graft direction mismatch on days 30 and 100 post-transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor-recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell-mediated protection against CMV reactivation.

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Section: Discussionmentioning

confidence: 99%

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Zhao

Luo

et al. 2017

Br J Haematol

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“…Patients with at least one C1 epitope transplanted from cord blood with C1 and KIR2DL2/L3/S2 had earlier recovery of licensed NK cells and less relapses. 46 The different observations in different studies is explained by differences in regimen intensities, donor type and HLA-matching, stem cell source, T-cell content of the graft as well as stem cell and NK cell content. Most studies used myeloablative conditioning.…”

Section: Discussionmentioning

confidence: 99%

Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning

et al. 2017

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Reduced-toxicity conditioning with fludarabine and treosulfan is a dose-intensive regimen with enhanced anti-leukemia effect and acceptable toxicity in AML/MDS. HLA-C regulates natural-killer (NK) cell function by inhibiting Killer immunoglobulin-like receptors (KIR) and is divided into C1 and C2 epitopes. The missing-ligand theory suggests that missing recipient KIR ligands drives NK-alloreactivity after SCT, in the absence of HLA-mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched-siblings (n = 97) or matched-unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m ). 34% expressed one HLA-C group 1 allele (C1C1), 19% one HLA-C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow-up was 48 months. 5-year relapse, nonrelapse mortality (NRM) and leukemia-free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate-analysis identified chemo-refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA-C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA-C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA-matched SCT with treosulfan conditioning in AML/MDS.

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“…Recently, Sekine et al (39) reported that only patients homozygous for HLA-C2 group alleles had a higher 1-year relapse rate and worse survival after UCBT than did HLA-C1/C1 or HLA-C1/C2 patients. Unlike our work, two UCB units were used in almost all the patients of this study and they use the dominant engrafting unit of the two to determine the KIR-ligand compatibility.…”

Section: Discussionmentioning

confidence: 99%

Patients Lacking a KIR-Ligand of HLA Group C1 or C2 Have a Better Outcome after Umbilical Cord Blood Transplantation

et al. 2017

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Donor natural killer (NK) cells can destroy residual leukemic cells after allogeneic hematopoietic stem cell transplantation. This effect is based on the interaction of killer-cell immunoglobulin-like receptors (KIR) of donor NK cells with ligands of the major histocompatibility complex found on the surface of the target cells. HLA-C1 subtypes provide the ligand for KIR2DL2 and KIR2DL3 and the HLA-C2 subtypes for KIR2DL1. We have studied the probability of relapse (PR) after single-unit unrelated cord blood transplantation (UCBT) in relation to the potential graft-vs.-leukemia effect mediated by NK cells present in the umbilical cord blood (UCB) by analyzing KIR-ligand and HLA-C typing of the receptor. Data from 33 consecutive patients given a single unit UCBT were included. We have considered two groups of patients based on the absence or the presence of one of the C-ligands for inhibitory KIR and the incompatibility HLA-C1/2 between UCB and patients. Group 1 (n = 21): the patient lacks a C-ligand for inhibitory KIR present in UCB NK cells, i.e., patients homozygous C1/C1 or C2/C2. Group 2 (n = 12): patients heterozygous C1/C2 in which KIR-mediated graft-vs.-leukemia effect is not expected (presence of both C ligands for inhibitory KIR in the receptor). With a median follow-up post-UCBT of 93 months, patients with absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower actuarial PR than patients with both C-ligands (group 2): 21 ± 10 vs. 68 ± 18% at 2 year and 36 ± 13 vs. 84 ± 14% at 5 years (p = 0.025), respectively. In patients with acute lymphoblastic leukemia, the 2-year PR was 36 ± 21% for group 1 and 66 ± 26% for 2 (p = 0.038). Furthermore, group 1 had a lower incidence of grades II–IV acute graft-vs.-host disease (p = 0.04). In the setting of UCBT, the absence of a C-ligand (C1 or C2) of inhibitory KIR in the patient is associated with lower PR, which is probably due to the graft-vs.-host leukemia effect caused by UCB NK cells that lack a ligand for the inhibitory KIR 2DL1/2DL2/2DL3.

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Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation

Cited by 58 publications

References 41 publications

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Recipient‐donor KIR ligand matching prevents CMV reactivation post‐haploidentical T cell‐replete transplantation

Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning

Patients Lacking a KIR-Ligand of HLA Group C1 or C2 Have a Better Outcome after Umbilical Cord Blood Transplantation

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