The reactivity of natural killer cells and some T-cell populations is regulated by killer immunoglobulin-like receptors (KIR) interactions with target cell HLA class I molecules. Such interactions have been suggested to influence outcomes after allogeneic hematopoietic stem cell transplantation, particularly for myeloid malignancies and with T-cell depletion. Donor KIR genotypes and recipient HLA KIR ligands were analyzed in 60 AML patients receiving T-cell replete, HLA-matched-related donor allogeneic bone marrow transplants. Patients were categorized according to their HLA inhibitory KIR ligand groups by determining whether or not they expressed: HLA-A3 or -A11; HLA-Bw4 and HLA-Cw groups (homozygous C1, homozygous C2 or heterozygous C1/C2). Heterozygous C1/C2 patients had significantly worse survival than those homozygous for C1 or C2 (5.8 vs 43.5 months, respectively, P=0.018) and the C1/C2 group had a higher relapse rate (47 vs 31%, respectively, P=0.048). Multivariate analysis found C1/C2 status to be an independent predictor for mortality (P=0.007, HR 2.54, confidence interval 1.29–5.00). C1/C2 heterozygosity was also associated with a delayed time to platelet engraftment, particularly for those with concurrent HLA-Bw4 expression (P=0.003). Since C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK- and T-cell populations involved in graft vs leukemia responses.
Allogeneic hematopoietic stem cell transplantation (HSCT) has been a curative treatment modality for many patients with acute myeloid leukemia (AML).1, 2 The graft vs leukemia (GVL) effect has been attributed to donor-derived alloreactive immune cells including T-lymphocytes and natural killer (NK) cells.3, 4, 5, 6 The reactivity of NK cells and some T-lymphocyte subsets is regulated by the interaction of killer immunoglobulin-like receptors (KIRs) with target cell HLA-class I molecules.6 There are two forms of KIRs, either activating or inhibitory. Both forms share a common two- or three- subunit extracellular domain that binds to identical ligands. However, the inhibitory receptors are characterized by a cytoplasmic tail containing immunoreceptor tyrosine-based inhibitory motifs, whereas the activating KIRs lack a cytoplasmic tail but possess an adaptor protein (DAP12) with immunoreceptor tyrosine-based activating motifs.6, 7, 8 Upon engagement of an immune effector cell's KIR with its ligand, either an inhibitory or activating signal is generated depending on the functional status of the receptor. Inhibitory KIRs have a greater affinity for HLA-class I ligands and when concurrent ligation of both activating and inhibitory KIRs occurs the inhibitory signal predominates, which subsequently prevents NK cell-mediated target cell lysis.9
HLA-Cw is the main ligand for most inhibitory KIRs. Two HLA-Cw groups exist, C1 and C2, which are distinguished by their amino-acid residues at positions 77 and 80 in the α-1 helix of the HLA-C molecule.10 The C1 group is characterized by a serine at position 77 and an asparagine at position 80 and this includes HLA-Cw1, -Cw3, -Cw7 and -Cw8. The corresponding inhibitory receptors for the C1 group are KIR2DL2 and KIR2DL3, whereas the activating receptor is KIR2DS2. In contrast, the C2 group has an asparagine at position 77 and a lysine at position 80 and this includes HLA-Cw2, -Cw4, -Cw5 and -Cw6. The respective inhibitory receptor for the C2 group is KIR2DL1, whereas the activating receptor is KIR2DS1. Other human inhibitory KIRs with known ligands include KIR3DL1 that binds to the HLA-Bw4 epitope11 and KIR3DL2 that binds to HLA-A3 or HLA-A11.6
KIR interactions have been suggested to influence outcomes of haploidentical,5, 12 matched unrelated donor (MUD)13 and HLA-matched related donor (MRD) allogeneic HSCT,14, 15 particularly for AML patients. In general, these reports5, 12, 13, 15 have included heterogeneous disease populations and have employed TBI-based transplant preparative regimens with extensive T-cell depletion methods and/or antithymocyte globulin. In contrast, we investigated the role of donor KIR genotyping and recipient HLA-KIR ligand analysis in a more homogeneous population consisting only of AML patients who received a T-cell replete MRD allogeneic bone marrow transplant (BMT) after a non-TBI conditioning regimen. Furthermore, this is the first report to demonstrate that the rate of platelet engraftment correlates with the expression of HLA determinants that serve as ligands for inhibitory KIRs. This may suggest that the interaction of donor KIRs with recipient HLA–KIR ligands influences platelet engraftment after allogeneic haematopoietic stem cell transplantation.
Patients and methods
Between April 1997 and November 2003, 60 AML patients underwent MRD allogeneic BMT at the Cleveland Clinic Foundation. All patients and donors were treated on allogeneic BMT protocols that were reviewed and approved by the Cleveland Clinic Foundation's Institutional Review Board with signed informed consent obtained from all patients.
HLA and KIR typing
All patients and donors were HLA typed by serologic and DNA-based methods. Serologic HLA class I and II typing was performed by standard lymphocytotoxicity assays. HLA class I (HLA-A*, -B* and -Cw*) and II (DRB1*, DQB1*, DPB1*) typing was performed using commercial or local kits by polymerase chain reaction-sequence-specific probe (PCR-SSOP) (Lifecodes Corporation, Stamford, CT, USA or One Lambda, Inc., Los Angeles, CA, USA) and/or PCR-sequence specific priming (SSP) (Pel Freez, Brown Deer, WI, USA or Genovision, West Chester, PA, USA) according to the manufacturer's instructions. These methods provided intermediate-resolution allele assignment, and in some cases high-resolution allele assignment as well, that allowed assessment of KIR ligands. HLA-DRB1* typing was also performed by direct sequencing with PCR-sequence based typing as described previously.16, 17
KIR genotyping was performed by PCR–SSOP (One Lambda and/or PCR–SSP (Pel Freez) using commercial kits according to the manufacturer's instructions. This typing provided data for the presence or absence of KIR genes and limited information about particular KIR alleles or variants.
Patients were then categorized according to their HLA inhibitory KIR ligand groups by determining whether or not they expressed (1) HLA-A3 or -A11; (2) HLA-Bw4 and (3) HLA-Cw groups (homozygous C1, homozygous C2 or heterozygous C1/C2).6, 10, 11 Fifty-seven (95%) of the donor–recipient pairs had DNA samples available from which KIR genotyping was performed retrospectively to determine the donor inhibitory KIR (KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1 and KIR3DL2) and activating KIR (KIR2DS1, KIR2DS2) genotypes.
All patients received a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg)–based preparative regimen with T-cell replete bone marrow as the hematopoietic stem cell source. Cyclosporine A with either methotrexate or mycophenolate mofetil was administered to all patients after transplantation for graft-vs-host disease (GVHD) prophylaxis.
Complete remission was defined as no detectable evidence of AML by standard criteria, including morphologic review with immunophenotypic and/or cytogenetic analyses. GVHD grading was performed according to standard criteria for acute18 and chronic GVHD.19 Freedom from relapse (FFR) was defined as the time from the date of transplantation until that of first relapse. Overall survival (OS) was defined as the interval from the date of transplantation until that of death or last follow-up. Platelet engraftment was defined as unsustained platelet recovery >20 000/μl and >50 000/μl for at least 3 days.
Categorical variables are summarized as frequency counts and percentages; continuous variables are summarized as the median and range. Eight outcomes were assessed: presence of any acute GVHD, grade 3–4 acute GVHD, presence of any chronic GVHD, extensive chronic GVHD, RFS, OS, platelet engraftment >20 000/μl and >50 000/μl. The primary purpose of the analysis was to compare outcomes for each of three KIR ligands: HLA-A3/-A11 (present/absent), HLA-Bw4 (present/absent) and HLA-Cw (homozygous C1 or C2, heterozygous C1/C2). First, the Kaplan–Meier method was used to estimate each of the outcomes for each KIR ligand and groups were compared using the log-rank test. Continuous variables were compared using the Wilcoxon rank sum test; categorical variables were compared using the χ2 test. Next, Cox proportional hazards analysis was used to identify multivariable prognostic factors for survival and for platelet engraftment. A stepwise selection procedure was used with a variable entry criterion of P<0.10 and a variable retention criterion of P<0.05. Twelve variables were considered in the analysis, regardless of their significance in univariable analysis: age, gender, number of prior chemotherapy regimens, prior radiotherapy, months from diagnosis to transplant, disease status at transplant, donor–recipient gender, CD34+ cell dose, total nucleated cell (TNC) dose, HLA-Cw status, HLA-Bw4 status and HLA-A3/-A11 status. Results are summarized as the hazard ratio, 95% confidence interval, and P-value. All analyses were done using SAS® software. All statistical tests were two-sided, and P<0.05 was used to indicate statistical significance.
The median age was 45 years (range, 8–62 years) and 60% were not in complete remission at the time of transplant. There were 33 (55%) females and 27 (45%) males. The racial backgrounds included 57 (95%) Caucasians, two (3%) African Americans, and one (2%) Hispanic. The median time from diagnosis to transplant was 4.4 months (range, 0.2–25.6 months). The median cell doses infused were 2.61 × 108 TNC's/kg (range, 0.94–6.30 × 108/kg) and 1.94 × 106 CD34+ cells/kg (range, 0.35–5.87 × 106/kg).
HLA–KIR ligand analysis
Twenty-five (42%) patients expressed HLA-A3 and/or HLA-A11. When these recipients were compared to those who did not express HLA-A3/-A11, no differences were found between the groups regarding the incidence of acute GVHD (P=0.31), grade 3–4 acute GVHD (P=0.75), chronic GVHD (P=0.74), extensive chronic GVHD (P=0.82), relapse (P=0.99) or death (P=0.43; Figure 1a).
Twenty-nine (48%) patients expressed HLA-Bw4. When these recipients were compared to those who did not express HLA-Bw4, no differences were found between the groups regarding the incidence of acute GVHD (P=0.48), grade 3–4 acute GVHD (P=0.87), chronic GVHD (P=0.08), extensive chronic GVHD (P=0.39), relapse (P=0.67), or death (P=0.65; Figure 1b).
Twenty-six (44%) patients were homozygous for either C1 (19 patients) or C2 (seven patients) and 34 (56%) were heterozygous C1/C2. No differences were found between homozygous and heterozygous patients for acute or chronic GVHD (0.25⩽P⩽0.81). However, overall survival was significantly better for the homozygous C1 or C2 patients as compared to those who were heterozygous C1/C2 (median 43.5 vs 5.8 months, respectively, P=0.018) (Figure 1c). This survival difference could not be attributed to baseline patient characteristics (Tables 1 and 2) and it remained significant in multivariable analysis (Table 3). The C1/C2 heterozygous group also had a higher relapse rate compared with the C1 or C2 homozygous patients (47% vs 31%, P=0.048; Table 4, Figure 2).
No other significant differences in post-transplant outcomes were found between the C1 or C2 homozygous and the C1/C2 heterozygous patients (Table 4). The survival difference between these HLA-Cw groups could not be attributed to the presence or absence of HLA-Bw4 (Table 1, Figure 1d) or HLA-A3/-A11. Relapse was the most common cause of death (Table 4). The median follow-up among 21 survivors is 36.3 months (range, 7.8–72.4 months).
The Kaplan–Meier estimates of median time to platelet engraftment >20 000 and >50 000/μl were 23 days (n=50) and 30 days (n=45), respectively. Platelet engraftment was similar between patients who expressed and did not express HLA-A3 or -A11 (P=0.41 for engraftment >20 000/μl; P=0.18 for engraftment >50 000/μl). By Kaplan–Meier analysis, however, the estimated median time to platelet engraftment >50 000/μl was shorter for C1 or C2 homozygous patients compared with C1/C2 heterozygous patients (median, 27 vs 35 days, respectively, P=0.023) and was shorter for those who were HLA-Bw4 negative (n=31) compared with HLA-Bw4 positive (n=29) (median, 26 vs 38 days, respectively, P=0.015). Similarly, platelet engraftment >20 000/μl was shorter for C1 or C2 homozygous patients compared with C1/C2 heterozygous patients (median, 21 vs 26 days, respectively, P=0.049) whereas engraftment was more rapid for HLA-Bw4 negative recipients than those who were HLA-Bw4 positive (median, 21 vs 30 days, respectively, P=0.012).
Since both C1/C2 heterozygosity and HLA-Bw4 positive status correlated with longer time to platelet engraftment, the possible interaction of these two variables was next investigated. The analysis for platelet engraftment >20 000 and >50 000/μl suggested an additive effect. Patients lacking expression of both of these variables had the most rapid platelet engraftment (group 1; n=14), whereas those who expressed both variables had the slowest platelet engraftment (group 2; n=17), and those who expressed only one of the variables had an intermediate time to platelet engraftment (group 3; n=29) (Figure 3). These differences could not be attributed to the infused CD34+ cell doses (group 1: 2.02 × 106/kg; group 2: 1.87 × 106/kg; group 3: 1.92 × 106/kg; P=0.54 (Kruskal–Wallis test)) or the TNC doses (group 1: 2.64 × 108/kg; group 2: 2.60 × 108/kg; group 3: 2.62 × 108/kg; P=0.82).
Fifty-seven patient–donor cases had KIR genotyping performed for those KIRs with established HLA ligands. Every donor tested had at least one inhibitory KIR gene specific for an HLA–Cw ligand present in the recipient. Donors for the C1 homozygous patients were positive for the following KIRs: 79% KIR2DL2, 68% KIR2DL3 and 47% both KIR2DL2 and KIR2DL3. Among the C1 homozygous patients 16 (84%) had a donor whose genotype was positive for KIR2DL1. However, all 19 C1 homozygous patients had a donor whose genotype was positive for KIR2DL2 and/or KIR2DL3.
All donors for the C2 homozygous patients were positive for KIR2DL1 as well as for KIR2DL2 and/or KIR2DL3. Donors for the C1/C2 heterozygous patients were positive for the following KIRs: 84% KIR2DL1, 58% KIR2DL2 and 78% KIR2DL3. In this group, 16% were positive for one, 48% were positive for two and 36% were positive for all three of these inhibitory KIRs. The presence of the activating receptors KIR2DS1 or KIR2DS2 had no influence on outcomes in any of the HLA-Cw groups.
We also analyzed the data according to the receptor–ligand model20 with regard to relapse-free and overall survivals for the 57 patient–donor cases who had KIR genotyping available. Receptor–ligand mismatched patients (i.e., C1 homozygous patients with KIR2DL1 positive donors as well as the C2 homozygous patients with KIR2DL2 or KIR2DL3 positive donors; n=23) were compared to receptor–ligand matched patients (i.e., C1 homozygous patients with KIR2DL1 negative donors as well as all C1/C2 heterozygous patients regardless of the donor KIR genotypes; n=34). Although there were early differences between the two groups up to 3 years post-transplant in favor of the receptor–ligand mismatched patients, with further follow-up no significant differences in either relapse-free survival or overall survival were appreciated.
Each of the HLA-Cw groups was then analyzed to determine the incidence of a missing HLA-Bw4 ligand in donors positive for KIR3DL1. Among the C1 homozygous group, 13 (68%) patients were missing an HLA-Bw4 ligand and six of these died (two from relapsed AML, two from infection, one from GVHD and one from pulmonary toxicity). For the C2 homozygous group only one (14%) patient lacked an HLA-Bw4 ligand and died of lung carcinoma. Among the C1/C2 heterozygous patients 16 (52%) were missing an HLA-Bw4 ligand and 12 of these died (eight from relapsed AML, two from infection, one from GVHD and one from multiorgan failure).
The alloreactivity of donor-derived immune effector cells, including NK cells and some T-cell subsets, is mediated through the interaction of their KIRs with host HLA–KIR ligands. These interactions have been demonstrated to be important in patients undergoing HLA-mismatched allogeneic HSCT, particularly when the HLA-C locus is involved.5, 12, 13 More recently, there has also been evidence that these immune responses may influence outcomes in MRD allogeneic HSCT.14, 15 Although for MRDs the HLA types are identical for donors and recipients, the loci for KIRs and HLA are on different chromosomes that segregate independently. Therefore, disparities between the donor KIRs and the recipient HLA class I KIR-ligands can be anticipated.
The current report demonstrates that AML patients who were heterozygous C1/C2 had inferior overall survival after MRD allogeneic BMT compared to those who were homozygous for C1 or C2 alleles. This survival difference was correlated with a higher relapse rate in the heterozygous C1/C2 patients who had a much more rapid time to treatment failure (Figure 2). As C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK- and T-cell populations involved in GVL responses.
Our findings do not corroborate those described in a previous report that noted inferior survival in C2 homozygous patients.14 However, the majority of the patients with myeloid diseases in that series had CML or MDS. These diseases may have inherent biological differences from AML with regard to NK- and T-cell-mediated target cell lysis. Evidence to support this includes the higher response rates observed in patients with CML as compared to AML who receive donor lymphocyte infusions for disease relapses after allogeneic HSCT.21, 22, 23, 24 In addition, we and others15, 25 did not find that the combination of recipient C2 homozygous status and donor genotype containing the activating KIR2DS2 had an additive detrimental effect as suggested previously.14
HLA–Cw ligands have been demonstrated to be the major class I molecule important in NK cell-mediated immune responses after allogeneic HSCT.5, 6 Furthermore, there is evidence that absence of HLA-Bw4 may also result in improved post-transplant outcomes.15 Although the survival difference between our HLA–Cw ligand groups could not be attributed to an absence of HLA-Bw4 (Figure 1d), we did find this to have a significant effect on platelet engraftment.
Host immune effector cells such as CD8+, TCRαβ+ and TCRγδ+ T-lymphocytes as well as NK cells have been implicated in resistance to platelet engraftment.26, 27 However, the influence of KIR matching on platelet engraftment has not previously been well described. We speculate that donor-derived NK cells or T-cell subsets expressing inhibitory KIRs may suppress recipient immune cells that mediate resistance to platelet engraftment. The ability of these donor cells to control recipient platelet engraftment resistance may thus relate to the level of inhibitory KIR engagement. When minimal opportunity for inhibitory KIR engagement exists (C1 or C2 homozygous, HLA-Bw4 negative) maximal donor NK cell control of recipient cells is expected and rapid platelet engraftment ensues. Alternatively, when maximal opportunity for inhibitory KIR engagements exists (C1/C2 heterozygous, HLA-Bw4 positive) donor NK cell control of recipient cells may be reduced leading to delayed platelet engraftment (Figure 3).
A missing KIR ligand model for patients who received T-cell depleted HLA-identical sibling allogeneic HSCT indicated that 60% of donor-recipient pairs had a missing KIR ligand in the recipient.15 This finding resulted in improved disease-free and overall survivals in AML and MDS patients owing to lower relapse rates. An analysis of our patients revealed that there were no cases in which the donor did not have at least one inhibitory KIR gene specific for an HLA–Cw ligand present in the recipient. However, 30 (53%) of our donor-recipient pairs had a missing HLA-Bw4 KIR ligand and 33 (58%) had a missing HLA-A3 or -A11 KIR ligand. We did not find these missing KIR ligands to influence post-transplant outcomes. Our patients also received T-cell replete bone marrow, which provided an environment to examine interactions between donor KIRs and recipient HLA-KIR ligands, not only for NK cells, but also for T-cell subsets that have likewise been shown to express inhibitory KIRs.28, 29
As all of our tested donors had at least one inhibitory KIR gene specific for an HLA–Cw ligand present in the recipient the genotypic potential existed to inhibit all NK cells. However, it seems unlikely that none of these patients experienced a GVL effect. Variable levels of KIR expression may exist between different NK- and T-cell clones. Such clones may have mediated a GVL effect. Therefore, further investigation of KIR expression at the cellular level, rather than by KIR genotyping alone, should be pursued.20, 30 Epigenetic silencing and allele polymorphisms are potential mechanisms that may account for differences observed between genotyping and phenotyping.31, 32, 33, 34 A repertoire assessment of inhibitory KIRs by genotyping and phenotyping demonstrated discrepancies in approximately 25% of cases.30 Flow cytometric analysis, RNA-based gene expression methods and clonal-repertoire assessment have shown considerable variability in KIR cell surface expression and in the levels of transcripts among individuals expressing specific KIR genes.30
Assessment of KIRs and HLA–KIR ligand interactions has important implications not only for haploidentical and MUD allogeneic HSCT, but also for MRD transplants. The finding of C1/C2 heterozygosity as a poor prognostic factor for AML patients undergoing MRD allogeneic BMT suggests that additional approaches to intensify therapy (e.g., total body irradiation-based preparative regimens or prophylactic donor lymphocyte infusions for patients without GVHD) may be appropriate for such patients. Future approaches examining post-transplant outcomes in relation to specific KIR phenotypes may also be useful to more precisely define prognostic subgroups that may be considered when selecting a hematopoietic stem cell donor.
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Sobecks, R., Ball, E., Maciejewski, J. et al. Survival of AML patients receiving HLA-matched sibling donor allogeneic bone marrow transplantation correlates with HLA-Cw ligand groups for killer immunoglobulin-like receptors. Bone Marrow Transplant 39, 417–424 (2007) doi:10.1038/sj.bmt.1705609
- allogeneic BMT
- killer immunoglobulin-like receptors (KIRs)
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