Haematologica, Vol 94, Issue 10, 1427-1434 doi:10.3324/haematol.2009.008318
Copyright © 2009 by Ferrata Storti Foundation
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Stem Cell Transplantation

NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies

J. Luis Espinoza1, Akiyoshi Takami1, Makoto Onizuka2, Hiroshi Sao3, Hideki Akiyama4, Koichi Miyamura5, Shinichiro Okamoto6, Masami Inoue7, Yoshinobu Kanda8, Shigeki Ohtake1, Takahiro Fukuda9, Yasuo Morishima10, Yoshihisa Kodera11, Shinji Nakao1 for the Japan Marrow Donor Program

1 Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa
2 Department of Hematology and Oncology, Tokai University School of Medicine, Isehara
3 Department of Hematology, Meitetsu Hospital, Nagoya
4 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo
5 Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya
6 Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo
7 Department of Hematology and Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka
8 Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama
9 Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo
10 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya
11 Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagoya, Japan

Correspondence: Akiyoshi Takami, M.D., Ph.D., Department of Hematology & Oncology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, 920-8641, Japan. E-mail:takami{at}med3.m.kanazawa-u.ac.jp


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ABSTRACT
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 ABSTRACT
Introduction
 Design and Methods
 Results
 Discussion
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Background: NKG2D, an activating and co-stimulatory receptor expressed on natural killer cells and T cells, plays pivotal roles in immunity to microbial infections as well as in cancer immunosurveillance. This study examined the impact of donor and recipient polymorphisms in the NKG2D gene on the clinical outcomes of patients undergoing allogeneic T-cell-replete myeloablative bone marrow transplantation using an HLA-matched unrelated donor.

Design and Methods: The NKG2D polymorphism was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. The patients underwent transplantation following myeloablative conditioning; the recipients and donors were matched through the Japan Marrow Donor Program.

Results: In patients with standard-risk disease, the donor NKG2D-HNK1 haplotype, a haplotype expected to induce greater natural killer cell activity, was associated with significantly improved overall survival (adjusted hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85; p=0.01) as well as transplant related mortality (adjusted hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.86; p=0.02), but had no impact on disease relapse or the development of grade II–IV acute graft-versus-host disease or chronic graft-versus-host disease. The NKG2D polymorphism did not significantly influence the transplant outcomes in patients with high-risk disease.

Conclusions: These data suggest an association between the donor HNK1 haplotype and better clinical outcome among recipients, with standard-risk disease, of bone marrow transplants from HLA-matched unrelated donors.

Key words: NKG2D, HNK1, LNK1, unrelated donor, bone marrow transplantation, single nucleotide polymorphism.


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Introduction
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 ABSTRACT
 Introduction
Design and Methods
 Results
 Discussion
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Hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for a range of hematologic malignancies. Although the use of an HLA-matched unrelated donor is well accepted when an HLA-identical sibling donor is unavailable, the risk of transplantation- related complications may be increased.1 Despite improvements in clinical and supportive care, transplant- related life-threatening complications, including graft-versus-host disease (GVHD), infections and disease relapse, remain an enormous obstacle to overcome.2 Although HLA matching is the major genetic determinant of clinical outcome after allogeneic SCT, recent evidence suggests that non-HLA immune-associated genes are also implicated.3 Previous investigations have revealed that several single nucleotide polymorphisms (SNP) which affect individual immune response to infections and inflammatory reactions are associated with the risk of GVHD and transplant outcomes.4–15

NKG2D is an activating and co-stimulatory receptor belonging to the C-type lectin-like family of transmembrane proteins and is expressed as a homodimer on natural killer (NK) cells, CD8+ {alpha}β+ T cells, {gamma}{delta}+ T cells and activated macrophages.16–18 The ligands for NKG2D, such as MHC class I-chain related proteins (MICA and MICB), UL16 binding proteins are usually absent or expressed at very low levels in normal cells but are up-regulated by cellular stress including heat shock and microbial infections and are frequently expressed in epithelial tumor cells.19 Ligand engagement of NKG2D triggers cell-mediated cytotoxicity and co-stimulates cytokine production through a DAP10-phosphoinositol 3-kinase dependent pathway and plays an important role in the elimination of tumors and infected cells.16–18,20

Recently, SNP were identified between LNK1 and HNK1 haplotypes of the NKG2D gene.21 In Japanese individuals, the HNK1 haplotype is associated with greater activity of NK cells in the peripheral blood21,22 and a lower prevalence of cancers originating from epithelial cells.21,23,24 The present study investigates the impact of donor and recipient polymorphisms in the NKG2D gene on the clinical outcomes of patients undergoing allogeneic myeloablative bone marrow transplantation using an HLA allele-matched unrelated donor.


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Design and Methods
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 Introduction
 Design and Methods
Results
 Discussion
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Patients
NKG2D genotyping was performed on a total 145 recipients with hematologic malignancies and their unrelated donors who were part of the Japan Marrow Donor Program (JMDP). The recipients underwent transplantation, following myeloablative conditioning, with T-cell-replete marrow from an HLA-A, -B, -C, -DRB1 allele-matched donor between November 1995 and March 2000. HLA genotypes of the HLA-A, -B, -C, and -DRB1 alleles of the patients and donors were determined by the Luminex microbead method described previously. (Luminex 100 System; Luminex, Austin, TX, USA).25,26 No patient had a history of prior transplantation. The final clinical survey of these patients was completed by November 1, 2007. Diagnoses were acute myeloid leukemia (n=49; 34%), acute lymphoblastic leukemia (n=37; 26%), chronic myeloid leukemia (n=41; 28%), myelodysplastic syndrome (n=11; 8%) and malignant lymphoma (n=7; 5%), (Table 1). The recipients were defined as having standard risk disease if they had acute myeloid or lymphoblastic leukemia in first complete remission, malignant lymphoma in complete remission, chronic myeloid leukemia in any chronic phase or myelodysplastic syndrome. All other patients were designated as having high-risk disease. Myeloid malignancies included acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome, whereas lymphoid malignancies included acute lymphoblastic leukemia and malignant lymphomas. Cyclosporine or tacrolimus- based regimens were used in all patients for GVHD prophylaxis whereas anti-T-cell therapy, such as anti-thymocyte globulin and ex vivo T-cell depletion, was not. All patients and donors gave their written informed consent to molecular studies, according to the declaration of Helsinki, at the time of transplantation. The project was approved by the Institutional Review Board of Kanazawa University Graduate School of Medicine and the JMDP.


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  		Table 1. Characteristics of the donors and recipients.

NKG2D genotyping
NKG2D was genotyped using the TaqMan-Allelic discrimination method27 with a 9700-HT real time polymerase chain reaction (PCR) system (Applied Biosystems, Foster City, CA, USA) and results were analyzed using allelic discrimination software (Applied Biosystems). The genotyping assay was conducted in 96-well PCR plates. The amplification reaction contained template DNA, TaqMan universal master mix and a specific probe (product No. C_9345347_10; Applied Biosystems) for rs1049174, a single locus featuring a G-C substitution to distinguish between the HNK1 (G) and LNK1 (C) haplotypes of the NKG2D gene.21,23,24

Data management and statistical analysis
Data were collected by the JMDP using a standardized report form. Follow-up reports were submitted at 100 days, 1 year and annually after transplantation. Pre-transplant cytomegalovirus serostatus was routinely tested only in patients but not in their donors. Engraftment was confirmed by an absolute neutrophil count of more than 0.5x109/L for at least 3 consecutive days. Acute and chronic GVHD were diagnosed and graded using established criteria.28,29 Overall survival was defined as the number of days from transplantation to death from any cause. Disease relapse was defined as the number of days from transplantation to disease relapse. Transplant-related mortality was defined as death without relapse. Any patients who were alive at the last-follow-up date were censored. When collecting data, only the main cause of death was recorded if two or more causes were combined. Data on etiological agents of infections, postmortem changes and supportive care (including prophylaxis of infections and therapy of GVHD, which were given on an institutional basis), were not available for this cohort of patients. The analysis was performed using Excel 2007 (Microsoft Corp, Redmond, WA, USA), OriginPro version 8.0J (Lightstone Inc, Tokyo, Japan), and R (The R Foundation for Statistical Computing, Perugia, Italy).30 The probability of overall survival was calculated using the Kaplan-Meier method and compared using the log-rank test. The probabilities of transplant-related mortality, disease relapse, acute GVHD, chronic GVHD, and each cause of death were compared using the Grey test31 and analyzed using cumulative incidence analysis,30 considering relapse, death without disease relapse, death without acute GVHD, death without chronic GVHD, and death without each cause as respective competing risks. The analysis was stratified for patients with standard-risk disease and high-risk disease to take into account the already recognized prognostic differences. The variables considered were recipient age at time of transplantation, sex, recipient cytomegalovirus serostatus before transplantation, disease characteristics (disease type and disease lineage), donor characteristics (age, sex, sex compatibility, and ABO compatibility), transplant characteristics (total body irradiation-containing regimen, tacrolimus versus cyclosporine, and total nucleated cell count harvested per recipient weight). The median was used as the cut-off point for continuous variables. The {chi}2 test and Mann-Whitney test were used to compare results of two groups. The Hardy-Weinberg equilibrium for the NKG2D gene polymorphism was tested using the Haploview program.32 Multivariate Cox models were used to evaluate the hazard ratio associated with the NKG2D polymorphism. Covariates found to be statistically significant in univariate analyses (p≤0.10) were included in the models. For both the univariate and multivariate analyses, p values were two-sided and outcomes were considered to be statistically significant with p≤0.05.


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Frequencies of NKG2D haplotype
The NKG2D gene polymorphism was analyzed in 145 pairs of unrelated donors-recipients of bone marrow following myeloablative conditioning (Table 1). The haplotype frequencies of LNK1/LNK1, HNK1/LNK1 and HNK1/HNK1 were 43%, 42% and 15%, respectively in donors and 35%, 45% and 20%, respectively in recipients. These frequencies were similar to those reported in previous studies in Japanese populations21,24 and were in accordance with the Hardy-Weinberg equilibrium (p=0.80).

Transplant outcomes according to NKG2D haplotype
With a median follow-up of 115 months among survivors (range, 74 to 140 months), 30 recipients (21%) had relapsed or progressed and 62 (47%) had died. Three patients (2%) died before engraftment. The analysis of the influence of the NKG2D genotype on clinical outcomes after transplantation was stratified according to whether the recipients had standard-risk disease or high-risk disease to account for the already recognized prognostic difference. The overall survival at 5 years in patients with standard-risk disease was 63% while that of patients with high-risk disease was 44% (p=0.06). The 5-year cumulative incidences of trasplant-related mortality were 32% and 27%, respectively (p=0.33) and those of disease relapse were 10% and 31%, respectively (p=0.0006).

The transplant outcomes according to NKG2D genotype are summarized in Table 2. Patients with standard-risk disease receiving transplants from donors with the HNK1 haplotype had a significantly better 5-year overall survival (73% vs. 49%, p=0.01; Figure 1A) and lower transplant-related mortality rate (22% vs. 45%, p=0.02; Figure 1B) than those receiving transplants from donors without the HNK1 haplotype. No difference was noted in disease relapse in relation to the donors’ polymorphism (9% vs. 11%, p=0.81; Figure 1C) or in the development of grades II to IV acute GVHD (28% vs. 41%, p=0.25) or chronic GVHD (37% vs. 41%, p=0.83). When patients with acute myeloid leukemia or myelodysplastic syndrome were separately analyzed, there was still no difference in disease relapse in relation to NKG2D polymorphisms (data not shown). In patients with high-risk disease, the donor HNK1 haplotype had no significant effects on transplant outcomes (Table 2).


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  		Table 2. Univariate analysis of the association of NKG2D polymorphisms with clinical outcomes after transplantation.


Figure 10941427
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  		Figure 1. Kaplan-Meier analysis of (A) overall survival, (B) cumulative incidence of transplant-related mortality and (C) disease relapse after transplantation according to the donor NKG2D polymorphism in patients with standard-risk disease. Patients with donors with the HNK1 haplotype had better overall survival and lower transplant-related mortality. Donor haplotype had no significant impact on disease relapse.

Multivariate analysis
Any factors found to be significant in univariate analyses were included in the multivariate analysis. When patients with standard-risk disease were analyzed, the HNK1 haplotype in donors remained statistically significant in multivariate analyses for both overall survival and transplant-related mortality (Table 3). The presence of the HNK1 haplotype in the donor resulted in better overall survival (hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85; p=0.01) and transplant-related mortality (hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.86; p=0.02). The donor and recipient HNK1 haplotype did not significantly influence the transplant outcomes in patients with high-risk disease.


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  		Table 3. Multivariate analysis of the association of NKG2D polymorphisms with clinical outcomes after transplantation.

Main causes of death
The main causes of death according to the HNK1 haplotype of the donors and recipients are illustrated in Figure 2A for patients with standard-risk disease, and in Figure 2B for those with high-risk disease. In patients with standard-risk disease receiving transplants from HNK1-negative donors, the most frequent cause of death was acute GVHD, followed by interstitial pneumonia. Transplants from HNK1-positive donors resulted in a statistically significantly reduced incidence of death attributed to acute GVHD (Figure 3A; p=0.006) as well as a trend toward a lower incidence of death attributed to interstitial pneumonia (Figure 3B; p=0.09). Other causes of death did not differ according to the HNK1 haplotype.


Figure 20941427
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  		Figure 2. Main causes of death after transplantation according to the NKG2D polymorphism in patients with (A) standard-risk disease (B) high-risk disease.


Figure 30941427
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  		Figure 3. Cumulative incidence of deaths due to (A) acute GVHD and (B) interstitial pneumonia after transplantation in patients with standard-risk disease. The HNK1 haplotype in donors was associated with a significantly lower incidence of deaths due to acute GVHD (p=0.006) as well as a trend toward a lower incidence of deaths due to interstitial pneumonia (p=0.09).


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Discussion
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 Design and Methods
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 Discussion
References
 
The current study showed an association between the NKG2D-HNK1 haplotype in unrelated donors of HLA-matched myeloablative bone marrow transplants (haplotype frequency, 61%) and a significantly reduced transplant-related mortality and better overall survival for their recipients with standard-risk disease. The polymorphism of the donor NKG2D gene did not influence disease relapse or the development of grades II to IV acute GVHD or chronic GVHD in the patients. One possible explanation for the absence of the beneficial effects of the HNK1 haplotype in patients with high-risk disease may be that the number of cases in the study was insufficient for a meaningful assessment of the effect. Alternatively, disease progression may precede the emergence of the potential advantageous effects of the HNK1 donor haplotype that could protect the recipient from severe transplant-related complications. There was a larger difference in disease relapse between patients with standard-risk disease and those with high-risk disease: 10% and 31% at 3 years after transplantation, respectively.

NKG2D plays important roles in immunity to microbial infections and is especially prominent in controlling viral and bacterial infections.16 Therefore, the reduced transplant-related mortality in patients with standard-risk disease receiving grafts from donors with the HNK1 haplotype in this study might be a consequence of increased resistance to infections in the recipients. However, the hypothesis is too speculative because of the unavailability of data on causes of infections in this cohort. Further studies will be needed to clarify whether the HNK1 haplotype in donors can effectively protect patients against infections.

Several studies have shown that NK cell activity has an important role in the outcomes of patients undergoing allogeneic transplantation.33,34 Alloreactive NK cells reduced the risk of relapse of acute myeloid leukemia without increasing the incidence of GVHD, resulting in a marked improvement of event-free survival in a series of haploidentical transplant recipients.35,36 In HLA-identical sibling transplants, the absence of HLA-C and HLA-B ligand for donor-inhibitory killer immunoglobulin-like receptors (KIR) provided benefits in terms of survival and relapse of patients with acute myeloid leukemia and myelodysplastic syndrome in recipients of T-cell-depleted SCT.37 On the other hand, the JMDP found that KIR ligand mismatch was unfavorably correlated with relapse of leukemia and survival in patients undergoing T-cell-replete unrelated bone marrow transplants.38 All patients in the present study received grafts from an HLA-A, -B, and -C allele-matched donor, implying KIR ligand match between each patient and donor. It is an open question whether the NKG2D polymorphism could affect the outcomes of patients undergoing transplantation with KIR-mismatched grafts.

In this study, major and minor ABO incompatibilities between the donor and recipient tended to be associated with poorer transplant outcomes, regardless of the risk category of the disease. These findings are compatible with those of a previous study by the JMDP,39 although the impact of ABO incompatibilities on SCT outcomes is controversial.

This study also identified age as a significant predictive factor for transplant-related mortality in the patients with standard-risk disease. This is consistent with the results of a previous study40 showing that age over 35 years increased the risk of transplant-related mortality after allogeneic myeloablative SCT in high-risk patients.

A possible limitation of this study is the fact that no direct evidence is yet available regarding the ability of NKG2D polymorphisms to protect against microbial infections. The association observed between the NKG2D haplotype and transplant outcome might be due to another genetic polymorphism in linkage disequilibrium responsible for a better transplant outcome. One candidate gene is NKG2F (KLRC4), which is located in the NK complex region adjacent to the NKG2D gene, because an intrinsic SNP (rs2617171) in the gene has been reported to be in complete linkage with the NKG2D genotype.24 Alternatively, polymorphisms may not be directly associated with controlling infection, but rather may be associated with other factors, such as sensitivity to treatment against GVHD or protection against organ toxicities related to transplants, which also influence the transplant outcome. These hypotheses have yet to be verified give the insufficient evidence.

Polymorphisms in genes encoding for nucleotide-binding oligomerization domain 2 (NOD2)/caspase recruitment domain 15 (CARD15),9 heme oxygenase-1 (HO-1) promoter,6 the Toll-like receptor 4,4 CC chemokine ligand (CCL) 5 promoter,32 transforming growth factor (TGF) β1,11 interleukin (IL) 12, tumor necrosis factor (TNF) {alpha},15 IL-23,5 mannose-binding lectin (MBL),10 Fc{gamma} receptor IIa (Fc{gamma}RIIa), myeloperoxidase (MPO), Fc{gamma}RIIIb, IL-1Ra, IL-10,12 Fc receptor-like 3 (FCRL3), peptidylarginine deiminase citullinating enzymes 4 (PADI4)13 and methylenetetrahydrofolate reductase (MTHFR)14 have been shown to influence the outcome after allogeneic SCT. Most of them are associated with the development of GVHD. Only the NOD2/CARD15 and HO-1 promoter polymorphisms have a significant impact on overall survival after SCT. Furthermore, the impact of the HO-1 promoter polymorphisms depends on donor cells but not on recipient cells, as observed with the NKG2D polymorphism which, in the donor, was shown to be significantly associated with overall survival in the present study. This may prompt the determination of the donor NKG2D polymorphism prior to SCT in order to choose the best donor, expected to minimize transplant-related mortality after SCT, when multiple donors for a patient are available. Otherwise, prior information on the donor NKG2D polymorphism may be helpful in selecting risk-specific appropriate precautions following transplantation.

In conclusion, the present data suggest that the NKG2D polymorphism, in addition to HLA disparity between recipients and donors, affects prognosis after a bone marrow transplant from an unrelated donor. However, care should be made in drawing conclusions because the number of patients in the present study was small. The finding of a gene polymorphism may not be equivalent to differences in gene expression, which may be influenced by multiple factors because the NKG2D receptor is found on many tissues and cells.41 Experimental evidence is required to substantiate the effect of the NKG2D polymorphism on immune function. We next plan to conduct a prospective study to confirm these results and to extend this investigation to other transplantation settings, such as related donor SCT, reduced-intensity SCT, HLA-mismatched SCT and SCT for patients with non-hematologic malignancies.


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Acknowledgments
 
we are indebted to Drs. Hiroko Oshima, Masanobu Oshima and Atsushi Hirao, Mrs. Shinichi Ohmae and Katsuya Nakata, and Ms. Kaori Matsuura at Kanazawa University, and Drs. Keitaro Matsuo and Takakazu Kawase at the Aichi Cancer Center Research Institute for their technical assistance. We thank all of the JMDP transplant teams who contributed patients and donors to this study.


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Footnotes
 
Authorship and Disclosures

JLE and AT designed and performed the research, and contributed to the same aspects of the work; AT, JLE and SN wrote the paper; AT, YKa, and SOh performed the statistical analyses; MO, HS, HA, KM, SOk, MI, TF, YM, and YKo contributed to data collection.

The authors reported no potential conflicts of interest.

Funding: this study was supported by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports and Technology, and funds from the Mitani Research and Development Assistance Organization (Kanazawa, Japan) and by the Japan Leukemia Research Fund (Tokyo, Japan).

Received for publication March 5, 2009. Revision received April 13, 2009. Accepted for publication April 29, 2009.


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References
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 Design and Methods
 Results
 Discussion
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