KIR基因对异基因造血干细胞移植预后的影响及其机制研究的初步探讨
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摘要
第一部分KIR基因型、单倍型和受配体模式分析对异基因造血干细胞移植预后的影响
目的：建立杀伤细胞免疫球蛋白样受体(killer cell immunoglobulin receptor，KIR)基因型、单倍型及受配体缺失模式，分析其对异基因造血干细胞移植(allogeneichemotopoietic stem cell transplantation, allo-HSCT)预后的影响。
方法：采用序列特异性引物聚合酶链反应方法，对进行HLA-A、-B、-C、-DRB1、-DQB1高分辨的供、受者进行KIR检测，建立三种KIR分型模式(供受体KIR基因模式、KIR/HLA受配体缺失模式、供体KIR单倍体模式)。
结果：1.供受体KIR基因模式：即供者与受者KIR受体基因是否相合。当供受者KIR基因型完全相合时，即为供受体KIR基因相合。当供受者KIR不完全相合时即为供受者KIR基因错配。2.供受体KIR/HLA受配体模式分析：当受者缺乏与供者KIR相合的HLA配体时即为供受体KIR/HLA受配体缺失模式。3. KIR单体型分型：①A单体型：以抑制性KIR(iKIR)为主，仅有唯一的激活性KIR为KIR2DS4，KIR2DS4可进一步分为2DS4完整型、2DS4完整/缺失型、2DS4缺失型三组亚型；②B单体型：包含多种激活性KIR(aKIR)(KIR2DS1、KIR2DS2、KIR2DS3、KIR2DS5、KIR3DSl)的不同组合。KIR-A/A基因型仅包含A单体型，KIR-A/B基因型同时包含A单体型和B单体型，KIR-B/B基因型仅包含B单体型，A/B基因型和B/B基因型合称为B/x基因型。A/A基因型可分为AA-1(完整型)，AA-2(完整/缺失型)和AA-3(缺失型)。B单体型可分为15种不同的单体B1–B15。KIR单倍体根据其基因在着丝粒(centromeric，Cen)和端粒端(telomeric，Tel)的分布可进一步分析。
结论：供受体KIR基因型模式、供受体KIR/HLA受配体模式及供体KIR单倍体模式的建立对于分析KIR基因对异基因造血干细胞移植预后的影响具有重要意义。
第二部分KIR基因对恶性血液病患者同胞HLA全相合造血干细胞移植预后的影响
目的：探讨KIR基因型及单倍型对同胞全相合造血干细胞移植的影响。
方法：采用序列特异性引物聚合酶链反应方法，对219对HLA-A、-B、-C、-DRB1、-DQB1高分辨基因分型全相合的同胞供、受者进行KIR基因分型，分别应用供受体KIR基因模式、KIR/HLA受配体缺失模式、供体KIR单倍体模式及其着丝粒(Cen)和端粒端(Tel)分析KIR对同胞全相合造血干细胞移植预后的影响。
结果：2005年3月~2012年10月在苏州大学附属第一医院接受同胞HLA全相合造血干细胞移植的219例患者中，男性120例，女性99例。其中AML111例，MDS17例，ALL40例，CML33例，NHL18例。中位年龄38岁(8岁~63岁)。中位随访时间14月(3月~93月)，6例失访。所有患者均接受清髓性预处理。192例患者接受BuCy预处理，27例患者接受TBI+Cy预处理。回输干细胞量CD34+细胞：3.79(1.36-12.0)×106/kg。五年总生存率(OS)为76.2%，无复发生存率(RFS)为69.6%。AML/MDS, ALL和CML的OS分别为72.7%，67.9%和93.5%(P=0.156)。
在供受体KIR基因模式中，供受体KIR基因不合组5年OS明显高于相合组(87.3%vs.69.3%; P=0.0268)，Ⅲ-Ⅳ急性GVHD低于相合组(4.6%vs.13.6%; P=0.029)。在KIR/HLA受配体缺失模式中，受体HLA为C1组与C2组比较，急性GVHD的发生率明显下降(23.2%vs.43.2%; P=0.002),在AML患者中效果更显著(21.5%vs.49.0%; P=0.001)。在供体KIR单倍型模式中，供体KIR基因型为Bx1者预后最差，和供体KIR基因型为其他Bx类型比较，其OS(100.0%vs.64.5%; P=0.0013)和RFS (100.0%vs.62.2%; P=0.0005)明显降低。而Bx1基因型的B单倍体位于端粒端，故进一步分析KIR的B单倍体位于端粒端和着丝粒端时对预后的影响。结果显示当供体KIR含有着丝粒端的B单倍体(Cen-B)时，移植的预后较好，OS (96.6%vs.72.0%; P=0.0169)和RFS(96.9%vs.61.3%; P=0.0056)明显提高，且复发率明显下降(2.9%vs.15.7%; P=0.047)。
同胞HLA全相合造血干细胞移植CMV感染率为34.2%(75/219)，中位感染时间为62天(26~265天)，其中CMV病毒血症发生率为4.6%(10/219)，3例患者发生CMV肺炎。供受体KIR基因相合组中受体移植后CMV激活发生率35.6%(47/132)，不合组CMV激活发生率32.2%(28/87)，两组间无统计学差异(P=0.663)。供体KIR基因为A/A型，受体移植后CMV激活发生率39.5%(49/124)，供体KIR基因为A/B型，CMV激活发生率30.3%(23/76)，供体KIR基因为B/B型，CMV激活发生率15.8%(3/19)。供体KIR基因为A/A型与B/B型比较，两者有统计学意义(P=0.036)。供体KIR含Tel-B时，移植后CMV激活发生率为24.4%(20/82)，明显低于供体无Tel-B时CMV激活率40.1%(55/137)(P=0.017)。
多因素分析提示供体KIR含Cen-B时OS (HR,8.293;95%CI,1.072–64.169; P=0.043)和RFS (HR:11.63;95%CI,1.51–89.566; P=0.018)明显提高，其作用主要体现在对复发的保护作用(HR,4.363;95%CI;1.184–16.08; P=0.027)。而受体HLA为C2是发生急性GVHD的危险因素(HR:0.316,95%CI:0.160–0.625, P=0.001)。分析KIR基因在ALL和CML患者移植的预后，其作用无统计学意义。
结论：同胞全相合造血干细胞移植是治疗恶性血液病的重要手段，但移植的预后却存在很大差异。本研究对KIR基因B单倍体进行着丝粒及端粒端分析，并第一次分析其对同胞HLA全相合造血干细胞移植预后的影响，结果提示供体KIR含有Cen-B时对复发有保护作用，从而提高生存率，改善预后。供受体KIR基因不合可改善同胞全相合造血干细胞移植的预后。在KIR/HLA受配体缺失模式中，受体HLA为C2是发生急性GVHD的危险因素。而上述KIR的作用在AML患者中效果更显著。
第三部分建立KIR/HLA受配体缺失体外模式及激活性KIR2DS4基因高表达的机制研究
目的：建立体外KIR-A/A型的自然杀伤(NK)细胞与树突状细胞(DC)共培养的模型，分析aKIR2DS4高表达的机制。
方法：检测受体HLA分型，分为HLA-C1组(C1/C1)和C2组(C1/C2和C2/C2)，在分选供体NK细胞前5~7天进行受体外周血单个核细胞衍生而来的DC培养；检测供体KIR基因，挑选KIR基因型为AA-1或AA-2的供体为实验组，KIR-A/B(2DS4Ful或Ful/Del)为对照组，分选供体CD3–CD16+CD56+NK细胞与DC共培养16~24小时，观察结果。
结果：供体NK细胞与受体DC细胞共培养后，当浓度达2.5:1及以上时，2DS4表达增高。在KIR-A/A组中，当NK细胞:DC细胞浓度达2.5:1及以上时，与NK(加IL-2)比较，2DS4表达明显升高(P=0.002)，而在KIR-A/B组中无此规律。供体为KIR-AA-1者NK细胞表面2DS4阳性率(74.4±14.8)%，AA-2者2DS4阳性率(37.7±30.6)%，两者有统计学差异(P=0.030)。当NK细胞与DC细胞按2.5:1共培养后，AA-1者2DS4表达升高(P=0.006)，按5:1共培养后，AA-1者2DS4表达升高(P=0.003)；AA-2者NK细胞与DC细胞按5:1共培养后2DS4表达也有升高(P=0.027)。NK细胞与C1组DC细胞共培养后，与NK(加IL-2)组相比，2DS4表达明显升高(P=0.009)，而与C2组DC细胞共培养后，2DS4表达略有升高，但无统计学意义(P=0.435)。
结论：本实验成功建立了KIR/HLA缺失的体外模型，并且证实当KIR/HLA发生错配时，活化型受体CD3–CD16+CD56+NK细胞直接杀伤靶细胞的异源反应活性增强，为前期的临床研究提供了理论依据，同时也为下一步NK细胞的功能试验奠定了基础。
PART Ⅰ Analysis of KIR Genotype, Haplotype, Receptor-LigandMismatch Model for Allogeneic Hematopoietic Stem CellTransplantation
Objective： To establish three different models of killer immunoglobulin-likereceptors (KIR) genotypes, haplotypes and receptor-ligand mismatches and to analyze theimpact on the prognosis of allogeneic hemotopoietic stem cell transplantation(allo-HSCT).
Methods: KIR and HLA genotypes were investigated in patient-donor pairsundergoing allo-HSCT. Three different models of KIR were established. There were KIRgenotype model, KIR haplotype model and receptor-ligand mismatch model.
Results:1. Donor and recipient KIR gene-gene mismatch model: A donor andrecipient KIR gene match was defined as the donor and the recipient having the same KIRgenotype. A donor and recipient KIR gene mismatch was defined as a KIR gene that waspresent in the donor and absent in the recipient or vice versa.2. Donor KIR receptor andrecipient ligand model: patients were categorized according to their HLA-inhibitory KIRligand groups by determining whether they expressed (1) HLA-A3or-A11,(2) HLA-Bw4,or (3) HLA-Cw groups (C1or C2).3. Donor KIR haplotype model contains A haplotypeand B haplotype. Individuals with only group A genes were assigned as A/A genotype.Individuals with either1(A/B heterozygous) or2(B/B homozygous) B haplotypes wereassigned the genotype as B/x genotype. Further subdivision of the A haplotype intosubgroups resulted in designation of A-1and A-2. The gene combinations of A-1and A-2can be divided into AA-1, AA-2, and AA-3. For group B, there were15differenthaplotypes named as B1–B15according to their frequencies. Donor centromeric andtelomeric KIR haplotype model contains Cen-A, Tel-A, Cen-B and Cen-B.
Conclusion: It is important to establish the three different models of KIR genotypes,haplotypes and receptor-ligand mismatches for analyzing the impact on the prognosis ofallo-HSCT.
PART Ⅱ Donor Selection for KIR Gene Mismatches and KIR BHaplotype of the Centromeric Motifs Can Improve the Outcome afterHLA-identical Sibling Hematopoietic Stem Cell Transplantation
Objective: After hematopoietic stem cell transplantation (HSCT), natural killer (NK)cell alloreactivity in human leukocyte antigen (HLA) cell of recipients is regulated bykiller immunoglobulin-like receptors (KIRs) on donor NK cells. The effect of KIRs onHSCT outcomes is controversial, particularly in those undergoing HLA-identical siblingHSCT.
Methods: KIR and HLA genotypes were investigated in a5-year retrospective studycomprising219patient-donor pairs undergoing HLA-identical sibling HSCT for myeloidand lymphoid malignancies.
Results: We found that39.7%of these pairs were mismatched for KIR with betteroverall survival (OS) and reduced Ⅲ-Ⅳ acute graft-versus-host disease (aGVHD),especially in acute myeloid leukemia (AML) patients. Bx1donor KIR genotype withhaplotype B on a telomeric region was a risk factor for OS and relapse-free survival (RFS).Donor centromeric and telomeric KIR haplotype analysis indicated an association of donorKIR B haplotype of the centromeric motifs (Cen-B) with improved OS and RFS and alower relapse rate. aGVHD was significantly lower in C1patients, especially for thosewith AML. No such effects were observed in patients with acute lymphoblastic leukemiaand chronic myelogenous leukemia.
We found that34.2%(75/219) patients had CMV reactivation after HLA-identicalsibling HSCT. The median time of CMV reactivation was62days (26~265days). Indonor-receptor KIR match group,35.6%(47/132) patients had CMV reactivation, while indonor-receptor KIR mismatch group, the CMV reactivation rate was32.2%(28/87)(P=0.663)。CMV reactivation rate was different depend on donor KIR genotype. The CMVreactivation rate was39.5%(49/124),30.3%(23/76) and15.8%(3/19) in donor KIRgenotype A/A, A/B and B/B, respectively (P=0.036)。Donor centromeric and telomericKIR haplotype analysis indicated an association of donor KIR B haplotype of the telomericmotifs a lower CMV reactivation rate,24.4%(20/82) versus40.1%(55/137)(P=0.017).
Conclusion: Our results suggest that KIR mismatches and a donor haplotype withCen-B confer significant survival benefits to HLA-identical sibling HSCT patients.
PART Ⅲ Establishing of in vitro KIR/HLA Receptor-Ligand MismatchModel and Analysis of Activating KIR2DS4in Allogeneic HematopoieticStem Cell Transplantation
Objective: To establish the in vitro KIR/HLA receptor-ligand mismatch model and toanalyze activating KIR2DS4in allo-HSCT.
Methods: HLA genotypes were investigated in patients, and then the patients weredivided into two groups: HLA-C1group (C1/C1and C1/C2) and C2group (C2/C2). DonorKIR genotypes were invastigated and donors with KIR AA-1and AA-2were inexperimental group, donors with KIR A/B (2DS4Ful or Ful/Del) were in control group.Immature DCs (iDC) were generated from patients’ peripheral blood mononuclear cell(PBMCs). After5~7days, donors’CD3–CD16+CD56+NK cells were separated. Donor’ NKcells and patients’ iDCs were cocultured in RPMIc medium at different ratios (NK/DC) for16~24hours.
Results：Donor’ NK cells and patients’ iDCs were cocultured in RPMIc medium atdifferent ratios. When the ratio was more than2.5:1, the expression of2DS4was increased.In A/A group, the expression of2DS4was increased (P=0.002), while we didn’t find thisincrease in B/x group. The positive rate of2DS4was (74.4±14.8)%in donor KIR AA-1group and (37.7±30.6)%in AA-2group (P=0.030). In AA-1group, the expression of2DS4was increased when NK/DC ratio was more than2.5:1compared with NKcell(without DC)(P=0.006)；In AA-2group, the expression of2DS4was increased whenNK/DC ratio was5:1compared with NK cell (without DC)(P=0.027). The expression of2DS4was significantly increased when Donor NK cells were cocultured with patients’iDCin C1-group (P=0.009). While in C2-group, the expression of2DS4was not increased (P=0.435).
Conclusion: This study established the in vitro KIR/HLA mismatch modelsuccessfully and confirmed that KIR/HLA mismatch could enhance the NK cellallo-reactivity, thus could guide the selection of the most suitable donor, prevention ofrelapse, GVHD and CMV infection, and will lay the foundation of NK cell functionalexperiment.
目的：建立杀伤细胞免疫球蛋白样受体(killer cell immunoglobulin receptor，KIR)基因型、单倍型及受配体缺失模式，分析其对异基因造血干细胞移植(allogeneichemotopoietic stem cell transplantation, allo-HSCT)预后的影响。
方法：采用序列特异性引物聚合酶链反应方法，对进行HLA-A、-B、-C、-DRB1、-DQB1高分辨的供、受者进行KIR检测，建立三种KIR分型模式(供受体KIR基因模式、KIR/HLA受配体缺失模式、供体KIR单倍体模式)。
结果：1.供受体KIR基因模式：即供者与受者KIR受体基因是否相合。当供受者KIR基因型完全相合时，即为供受体KIR基因相合。当供受者KIR不完全相合时即为供受者KIR基因错配。2.供受体KIR/HLA受配体模式分析：当受者缺乏与供者KIR相合的HLA配体时即为供受体KIR/HLA受配体缺失模式。3. KIR单体型分型：①A单体型：以抑制性KIR(iKIR)为主，仅有唯一的激活性KIR为KIR2DS4，KIR2DS4可进一步分为2DS4完整型、2DS4完整/缺失型、2DS4缺失型三组亚型；②B单体型：包含多种激活性KIR(aKIR)(KIR2DS1、KIR2DS2、KIR2DS3、KIR2DS5、KIR3DSl)的不同组合。KIR-A/A基因型仅包含A单体型，KIR-A/B基因型同时包含A单体型和B单体型，KIR-B/B基因型仅包含B单体型，A/B基因型和B/B基因型合称为B/x基因型。A/A基因型可分为AA-1(完整型)，AA-2(完整/缺失型)和AA-3(缺失型)。B单体型可分为15种不同的单体B1–B15。KIR单倍体根据其基因在着丝粒(centromeric，Cen)和端粒端(telomeric，Tel)的分布可进一步分析。
结论：供受体KIR基因型模式、供受体KIR/HLA受配体模式及供体KIR单倍体模式的建立对于分析KIR基因对异基因造血干细胞移植预后的影响具有重要意义。
第二部分KIR基因对恶性血液病患者同胞HLA全相合造血干细胞移植预后的影响
目的：探讨KIR基因型及单倍型对同胞全相合造血干细胞移植的影响。
方法：采用序列特异性引物聚合酶链反应方法，对219对HLA-A、-B、-C、-DRB1、-DQB1高分辨基因分型全相合的同胞供、受者进行KIR基因分型，分别应用供受体KIR基因模式、KIR/HLA受配体缺失模式、供体KIR单倍体模式及其着丝粒(Cen)和端粒端(Tel)分析KIR对同胞全相合造血干细胞移植预后的影响。
结果：2005年3月~2012年10月在苏州大学附属第一医院接受同胞HLA全相合造血干细胞移植的219例患者中，男性120例，女性99例。其中AML111例，MDS17例，ALL40例，CML33例，NHL18例。中位年龄38岁(8岁~63岁)。中位随访时间14月(3月~93月)，6例失访。所有患者均接受清髓性预处理。192例患者接受BuCy预处理，27例患者接受TBI+Cy预处理。回输干细胞量CD34+细胞：3.79(1.36-12.0)×106/kg。五年总生存率(OS)为76.2%，无复发生存率(RFS)为69.6%。AML/MDS, ALL和CML的OS分别为72.7%，67.9%和93.5%(P=0.156)。
在供受体KIR基因模式中，供受体KIR基因不合组5年OS明显高于相合组(87.3%vs.69.3%; P=0.0268)，Ⅲ-Ⅳ急性GVHD低于相合组(4.6%vs.13.6%; P=0.029)。在KIR/HLA受配体缺失模式中，受体HLA为C1组与C2组比较，急性GVHD的发生率明显下降(23.2%vs.43.2%; P=0.002),在AML患者中效果更显著(21.5%vs.49.0%; P=0.001)。在供体KIR单倍型模式中，供体KIR基因型为Bx1者预后最差，和供体KIR基因型为其他Bx类型比较，其OS(100.0%vs.64.5%; P=0.0013)和RFS (100.0%vs.62.2%; P=0.0005)明显降低。而Bx1基因型的B单倍体位于端粒端，故进一步分析KIR的B单倍体位于端粒端和着丝粒端时对预后的影响。结果显示当供体KIR含有着丝粒端的B单倍体(Cen-B)时，移植的预后较好，OS (96.6%vs.72.0%; P=0.0169)和RFS(96.9%vs.61.3%; P=0.0056)明显提高，且复发率明显下降(2.9%vs.15.7%; P=0.047)。
同胞HLA全相合造血干细胞移植CMV感染率为34.2%(75/219)，中位感染时间为62天(26~265天)，其中CMV病毒血症发生率为4.6%(10/219)，3例患者发生CMV肺炎。供受体KIR基因相合组中受体移植后CMV激活发生率35.6%(47/132)，不合组CMV激活发生率32.2%(28/87)，两组间无统计学差异(P=0.663)。供体KIR基因为A/A型，受体移植后CMV激活发生率39.5%(49/124)，供体KIR基因为A/B型，CMV激活发生率30.3%(23/76)，供体KIR基因为B/B型，CMV激活发生率15.8%(3/19)。供体KIR基因为A/A型与B/B型比较，两者有统计学意义(P=0.036)。供体KIR含Tel-B时，移植后CMV激活发生率为24.4%(20/82)，明显低于供体无Tel-B时CMV激活率40.1%(55/137)(P=0.017)。
多因素分析提示供体KIR含Cen-B时OS (HR,8.293;95%CI,1.072–64.169; P=0.043)和RFS (HR:11.63;95%CI,1.51–89.566; P=0.018)明显提高，其作用主要体现在对复发的保护作用(HR,4.363;95%CI;1.184–16.08; P=0.027)。而受体HLA为C2是发生急性GVHD的危险因素(HR:0.316,95%CI:0.160–0.625, P=0.001)。分析KIR基因在ALL和CML患者移植的预后，其作用无统计学意义。
结论：同胞全相合造血干细胞移植是治疗恶性血液病的重要手段，但移植的预后却存在很大差异。本研究对KIR基因B单倍体进行着丝粒及端粒端分析，并第一次分析其对同胞HLA全相合造血干细胞移植预后的影响，结果提示供体KIR含有Cen-B时对复发有保护作用，从而提高生存率，改善预后。供受体KIR基因不合可改善同胞全相合造血干细胞移植的预后。在KIR/HLA受配体缺失模式中，受体HLA为C2是发生急性GVHD的危险因素。而上述KIR的作用在AML患者中效果更显著。
第三部分建立KIR/HLA受配体缺失体外模式及激活性KIR2DS4基因高表达的机制研究
目的：建立体外KIR-A/A型的自然杀伤(NK)细胞与树突状细胞(DC)共培养的模型，分析aKIR2DS4高表达的机制。
方法：检测受体HLA分型，分为HLA-C1组(C1/C1)和C2组(C1/C2和C2/C2)，在分选供体NK细胞前5~7天进行受体外周血单个核细胞衍生而来的DC培养；检测供体KIR基因，挑选KIR基因型为AA-1或AA-2的供体为实验组，KIR-A/B(2DS4Ful或Ful/Del)为对照组，分选供体CD3–CD16+CD56+NK细胞与DC共培养16~24小时，观察结果。
结果：供体NK细胞与受体DC细胞共培养后，当浓度达2.5:1及以上时，2DS4表达增高。在KIR-A/A组中，当NK细胞:DC细胞浓度达2.5:1及以上时，与NK(加IL-2)比较，2DS4表达明显升高(P=0.002)，而在KIR-A/B组中无此规律。供体为KIR-AA-1者NK细胞表面2DS4阳性率(74.4±14.8)%，AA-2者2DS4阳性率(37.7±30.6)%，两者有统计学差异(P=0.030)。当NK细胞与DC细胞按2.5:1共培养后，AA-1者2DS4表达升高(P=0.006)，按5:1共培养后，AA-1者2DS4表达升高(P=0.003)；AA-2者NK细胞与DC细胞按5:1共培养后2DS4表达也有升高(P=0.027)。NK细胞与C1组DC细胞共培养后，与NK(加IL-2)组相比，2DS4表达明显升高(P=0.009)，而与C2组DC细胞共培养后，2DS4表达略有升高，但无统计学意义(P=0.435)。
结论：本实验成功建立了KIR/HLA缺失的体外模型，并且证实当KIR/HLA发生错配时，活化型受体CD3–CD16+CD56+NK细胞直接杀伤靶细胞的异源反应活性增强，为前期的临床研究提供了理论依据，同时也为下一步NK细胞的功能试验奠定了基础。
PART Ⅰ Analysis of KIR Genotype, Haplotype, Receptor-LigandMismatch Model for Allogeneic Hematopoietic Stem CellTransplantation
Objective： To establish three different models of killer immunoglobulin-likereceptors (KIR) genotypes, haplotypes and receptor-ligand mismatches and to analyze theimpact on the prognosis of allogeneic hemotopoietic stem cell transplantation(allo-HSCT).
Methods: KIR and HLA genotypes were investigated in patient-donor pairsundergoing allo-HSCT. Three different models of KIR were established. There were KIRgenotype model, KIR haplotype model and receptor-ligand mismatch model.
Results:1. Donor and recipient KIR gene-gene mismatch model: A donor andrecipient KIR gene match was defined as the donor and the recipient having the same KIRgenotype. A donor and recipient KIR gene mismatch was defined as a KIR gene that waspresent in the donor and absent in the recipient or vice versa.2. Donor KIR receptor andrecipient ligand model: patients were categorized according to their HLA-inhibitory KIRligand groups by determining whether they expressed (1) HLA-A3or-A11,(2) HLA-Bw4,or (3) HLA-Cw groups (C1or C2).3. Donor KIR haplotype model contains A haplotypeand B haplotype. Individuals with only group A genes were assigned as A/A genotype.Individuals with either1(A/B heterozygous) or2(B/B homozygous) B haplotypes wereassigned the genotype as B/x genotype. Further subdivision of the A haplotype intosubgroups resulted in designation of A-1and A-2. The gene combinations of A-1and A-2can be divided into AA-1, AA-2, and AA-3. For group B, there were15differenthaplotypes named as B1–B15according to their frequencies. Donor centromeric andtelomeric KIR haplotype model contains Cen-A, Tel-A, Cen-B and Cen-B.
Conclusion: It is important to establish the three different models of KIR genotypes,haplotypes and receptor-ligand mismatches for analyzing the impact on the prognosis ofallo-HSCT.
PART Ⅱ Donor Selection for KIR Gene Mismatches and KIR BHaplotype of the Centromeric Motifs Can Improve the Outcome afterHLA-identical Sibling Hematopoietic Stem Cell Transplantation
Objective: After hematopoietic stem cell transplantation (HSCT), natural killer (NK)cell alloreactivity in human leukocyte antigen (HLA) cell of recipients is regulated bykiller immunoglobulin-like receptors (KIRs) on donor NK cells. The effect of KIRs onHSCT outcomes is controversial, particularly in those undergoing HLA-identical siblingHSCT.
Methods: KIR and HLA genotypes were investigated in a5-year retrospective studycomprising219patient-donor pairs undergoing HLA-identical sibling HSCT for myeloidand lymphoid malignancies.
Results: We found that39.7%of these pairs were mismatched for KIR with betteroverall survival (OS) and reduced Ⅲ-Ⅳ acute graft-versus-host disease (aGVHD),especially in acute myeloid leukemia (AML) patients. Bx1donor KIR genotype withhaplotype B on a telomeric region was a risk factor for OS and relapse-free survival (RFS).Donor centromeric and telomeric KIR haplotype analysis indicated an association of donorKIR B haplotype of the centromeric motifs (Cen-B) with improved OS and RFS and alower relapse rate. aGVHD was significantly lower in C1patients, especially for thosewith AML. No such effects were observed in patients with acute lymphoblastic leukemiaand chronic myelogenous leukemia.
We found that34.2%(75/219) patients had CMV reactivation after HLA-identicalsibling HSCT. The median time of CMV reactivation was62days (26~265days). Indonor-receptor KIR match group,35.6%(47/132) patients had CMV reactivation, while indonor-receptor KIR mismatch group, the CMV reactivation rate was32.2%(28/87)(P=0.663)。CMV reactivation rate was different depend on donor KIR genotype. The CMVreactivation rate was39.5%(49/124),30.3%(23/76) and15.8%(3/19) in donor KIRgenotype A/A, A/B and B/B, respectively (P=0.036)。Donor centromeric and telomericKIR haplotype analysis indicated an association of donor KIR B haplotype of the telomericmotifs a lower CMV reactivation rate,24.4%(20/82) versus40.1%(55/137)(P=0.017).
Conclusion: Our results suggest that KIR mismatches and a donor haplotype withCen-B confer significant survival benefits to HLA-identical sibling HSCT patients.
PART Ⅲ Establishing of in vitro KIR/HLA Receptor-Ligand MismatchModel and Analysis of Activating KIR2DS4in Allogeneic HematopoieticStem Cell Transplantation
Objective: To establish the in vitro KIR/HLA receptor-ligand mismatch model and toanalyze activating KIR2DS4in allo-HSCT.
Methods: HLA genotypes were investigated in patients, and then the patients weredivided into two groups: HLA-C1group (C1/C1and C1/C2) and C2group (C2/C2). DonorKIR genotypes were invastigated and donors with KIR AA-1and AA-2were inexperimental group, donors with KIR A/B (2DS4Ful or Ful/Del) were in control group.Immature DCs (iDC) were generated from patients’ peripheral blood mononuclear cell(PBMCs). After5~7days, donors’CD3–CD16+CD56+NK cells were separated. Donor’ NKcells and patients’ iDCs were cocultured in RPMIc medium at different ratios (NK/DC) for16~24hours.
Results：Donor’ NK cells and patients’ iDCs were cocultured in RPMIc medium atdifferent ratios. When the ratio was more than2.5:1, the expression of2DS4was increased.In A/A group, the expression of2DS4was increased (P=0.002), while we didn’t find thisincrease in B/x group. The positive rate of2DS4was (74.4±14.8)%in donor KIR AA-1group and (37.7±30.6)%in AA-2group (P=0.030). In AA-1group, the expression of2DS4was increased when NK/DC ratio was more than2.5:1compared with NKcell(without DC)(P=0.006)；In AA-2group, the expression of2DS4was increased whenNK/DC ratio was5:1compared with NK cell (without DC)(P=0.027). The expression of2DS4was significantly increased when Donor NK cells were cocultured with patients’iDCin C1-group (P=0.009). While in C2-group, the expression of2DS4was not increased (P=0.435).
Conclusion: This study established the in vitro KIR/HLA mismatch modelsuccessfully and confirmed that KIR/HLA mismatch could enhance the NK cellallo-reactivity, thus could guide the selection of the most suitable donor, prevention ofrelapse, GVHD and CMV infection, and will lay the foundation of NK cell functionalexperiment.
引文
1. Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity inHLA-mismatched hematopoietic stem cell transplantation. Blood,1999,1,94:333-339.
2. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
3. Farag SS, Fehniger TA, Ruggeri L et al. Nature kill cell receptor: new biology andinsights into the graft-versus leukemia effect. Blood,2002,15,100:1935-1947.
4. Giebel S, Dziaczkowska J, Czerw T, et al. Sequential recovery of NK cell receptorrepertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant,2010,45:1022-1030.
5. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
6. Norman PJ, Abi-Rached L, Gendzekhadze K, et al. Meiotic recombination generatesrich diversity in NK cell receptor genes, alleles, and haplotypes. Genome Res,2009,19:757-769.
7. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
8. Pende D, Marcenaro S, Falco M, et al. Anti-leukemia activity of alloreactive NK cellsin KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation ofthe functional role of activating KIR and redefinition of inhibitory KIR specificity.Blood,2009;113:3119-3129.
9. Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory andactivating Killer Ig-Like Receptors(KIR) on high-risk patients with myeloid andlymphoid malignancies undergoing reduced intensity transplantation fromhaploidentical related donors. Bone Marrow Transplantation,2012,47:817-823.
10. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
11. Giebel S, Loeatelli F, LamParelli T, et al. Survival advantage with KIR ligandincompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood,2003,102:814-819.
12. Miller JS, Cooley S, Parham P, et al. Missing KIR ligands are associated with lessrelapse and inereased graft-versus-host disease (GVHD) following unrelated donorallogeneic HCT. Blood,2007,109:5058-5061.
13. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
14. Cook MA, Milligan DW, Fegan CD, et al. The impact of donor KIR and patientHLA-C genotypes on outcome following HLA-identical sibling hematopoietic stemcell transplantation for myeloid leukemia. Blood,2004,103:1521-1526.
15. Wongwuttisaroj N, Vejbaesya S, Chongkolwatana V, et al. Analysis of KIR genes inHLA-identical sibling hematopoietic stem cell transplantation in Thai patients withleukemia. J Med Assoc Thai,2012,95:1261-1265.
16. Dou LP, Zheng DH, Wang C, et al. The diversity of KIR gene in Chinese NorthernHan population and the impact of donor KIR and patient HLA genotypes on outcomefollowing HLA-identical sibling allogeneic hematopoietic stem cell transplantation forhematological malignancy in Chinese people. Int J Hematol,2008,87:422-433.
17. Sobecks RM, Ball EJ, Maciejewski JP, et al. Survival of AML patients receivingHLA-matched sibling donor allogeneic bone marrow transplantation correlates withHLA-Cw ligand groups for killer immunoglobulin-like receptors. Bone MarrowTransplantation,2007,39:417-424.
18. U. Kanga, M. Mourya, T. Seth, et al. Role of Killer Immunoglobulin-likeReceptor-Ligand Interactions in Human Leukocyte Antigen–Matched SiblingHematopoietic Stem Cell Transplantation. Transplantation Proceedings,2012,44:919-921.
19. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
20. Chen C, Busson M, Rocha V. Activating KIR genes are associated with CMVreactivation and survival after non-T-cell depleted HLA-identical sibling bone marrowtransplantation for malignant disorders. Bone Marrow Transplantation,2006,38:437-444.
21. Cook M, Briggs D, Craddock C, et al. Donor KIR genotype has a major influence onthe rate of cytomegalovirus reactivation following T-cell replete stem celltransplantation. Blood,2006,107:1230-1232.
22. Zaia JA, Sun JY, Gallez-Hawkins GM, et al. The effect of single and combinedactivating KIR genotypes on CMV infection and immunity after hematopoietic celltransplantation. Bio Blood Marrow Transplant,2009,15:315-325.
23. Xiaojin Wu，Jun He，Depei Wu，et al. KIR and HLA-Cw genotypes of donor-recipientpairs influence the rate of CMV reactivation following non-T-cell deleted unrelateddonor hematopoietic cell transplantation. American Journal of Hematology,2009,84:776-777.
24. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant2010,45:1435-1441.
25.鲍晓晶,何军,孙爱宁等. KIR2DS4等位基因在无关全相合异基因造血干细胞移植中的作用.中华血液学杂志,2010,31:726-732.
1. Farag SS, Fehniger TA, Ruggeri L et al. Nature kill cell receptor: new biology andinsights into the graft-versus leukemia effect. Blood,2002,15,100:1935-1947.
2. Béziat V, Descours B, Parizot C, et al. NK cell terminal differentiation: correlatedstepwise decrease of NKG2A and acquisition of KIRs. PLoS One,2010,6,5: e11966.
3. Martin AM, Kulski JK, Gaudieri S, et al. Comparative genomic analysis, diversity andevolution of two KIR haplotypes A and B. Gene,2004,335:121-131.
4. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
5. X Bao, M Wang, H Zhou, et al. Characterization of killer cell immunoglobilin-likereceptor (KIR) genotypes and haplotypes in Chinese Han population. Tissu Antigen,2013,82:327-337.
6. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
7. Norman PJ, Abi-Rached L, Gendzekhadze K, et al. Meiotic recombination generatesrich diversity in NK cell receptor genes, alleles, and haplotypes. Genome Res,2009,19:757-769.
8. Hauch M, Gazzola MV, Small T, et al. Anti-leukemia potential of interleukin-2activated natural killer cells after bone marrow transplantation for chronicmyelogenous leukemia. Blood,1990,75:2250-2262.
9. Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity inHLA-mismatched hematopoietic stem cell transplantation. Blood,1999,94:333-339.
10.鲍晓晶,何军,陈子兴,等．非亲缘性HLA全相合的造血干细胞移植中供者-受者NK细胞KIR受体的研究.中华血液学杂志,2007,28:510-513.
11. McQueen KL, Dorighi KM, Guethlein LA, et al. Donor-Recipient Combinations ofGroup A and B KIR Haplotypes and HLA Class I Ligand Affect the Outcome ofHLA-Matched, Sibling Donor Hematopoietic Cell Transplantation. Hum Immunol,2007,68:309-323.
12. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
13. Gagne K, Brizard G, Gueglio B, et al. Relevance of KIR gene polymorphisms in bonemarrow transplantation outcome. Human Immunology,2002,63:271-280.
14. Ruggeri L, Mancusi A, Capanni M, et al. Donor natural killer cell allorecognition ofmissing self in haploidentical hematopoietic transplantation for acute myeloidleukemia: challenging its predictive value. Blood,2007,110:433-440.
15. Ljunggren HG, K rre K. In search of the 'missing self': MHC molecules and NK cellrecognition. Immunol Today,1990,11:237-244.
16. Giebel S, Dziaczkowska J, Czerw T, et al. Sequential recovery of NK cell receptorrepertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant,2010,45:1022-1030.
17. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
18. Siegler U, Kalberer CP, Nowbakht P, et al. Activated natural killer cells from patientswith acute myeloid leukemia are cytotoxic against autologous leukemic blasts inNOD/SCID mice. Leukemia,2005,19:2215-2222.
19. Bottino C, Castriconi R, Pende D, et al. Identification of PVR (CD155) and Nectin-2(CD112) as cell surface ligands for the human DNAM-1(CD226) activating molecule.J Exp Med,2003,18;198:557-567.
20. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes inresolving hepatitis C virus infection. Science,2004,6,305:872-874.
21. Littera R, Orrù N, Vacca A, et al. The role of killer immunoglobulin-like receptorhaplotypes on the outcome of unrelated donor haematopoietic SCT for thalassaemia.Bone Marrow Transplant,2010,45:1618-1624.
22. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
23. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
24. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cellreceptor genes leads to superior survival after unrelated transplantation for acutemyelogenous leukemia. Blood,2010,116:2411-2419.
25. Stringaris K, Adams S, Uribe M, et al. Donor KIR Genes2DL5A,2DS1and3DS1areassociated with a reduced rate of leukemia relapse after HLA-identical sibling stemcell transplantation for acute myeloid leukemia but not other hematologicmalignancies. Biol Blood Marrow Transplant,2010,16:1257-1264.
1. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matchingcontributes to the success of unrelated donor marrow transplantation. Blood,2007,110:4576-4583.
2. McQueen KL, Dorighi KM, Guethlein LA, et al. Donor-Recipient Combinations ofGroup A and B KIR Haplotypes and HLA Class I Ligand Affect the Outcome ofHLA-Matched, Sibling Donor Hematopoietic Cell Transplantation. Hum Immunol,2007,68:309-323.
3. Giebel S, Locatelli F, Lamparelli T, et al. Survival advantage with KIR ligandincompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood,2003,102:814-819.
4. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
5. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
6. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent anti-leukemic effectorcells after allogeneic bone marrow transplantation in mice. Transplantation,1995,59:1734-1736.
7. Tanaka J, Tutumi Y, Mori A, et al. Sequential analysis of HLA-C specific killer cellinhibitory receptor (CD158b) expressing peripheral blood mononuclear cells duringchronic graft-versus-host disease. Bone Marrow Transplant,2000,26:287-290.
8. Asai O, Longo DL, Tian Z, et al. Suppression of graft-versus-host disease andamplification of graft-versus-tumor effects by activated natural killer cells afterallogeneic bone marrow transplantation. J Clin Invest,1998,101:1835-1842.
9. Hauch M, Gazzola MV, Small T, et al. Anti-leukemia potential of interleukin-2activated natural killer cells after bone marrow transplantation for chronicmyelogenous leukemia. Blood,1990,75:2250-2262.
10. Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity inHLA-mismatched hematopoietic stem cell transplantation. Blood,1999,94:333-339.
11. Marsh SG, Parham P, Dupont B, et al. Killer-cell immunoglobulin-like receptor (KIR)nomenclature report.2002. Tissue Antigens,2003,62:79-86.
12. Hsu KC, Liu XR, Selvakumar A, et al. Killer Ig-like receptor haplotype analysis bygene content: evidence for genomic diversity with a minimum of six basic frameworkhaplotypes, each with multiple subsets. J Immunol,2002,169:5118-5129.
13. Pende D, Marcenaro S, Falco M, et al. Anti-leukemia activity of alloreactive NK cellsin KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation ofthe functional role of activating KIR and redefinition of inhibitory KIR specificity.Blood,2009,113:3119-3129.
14. Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory andactivating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid andlymphoid malignancies undergoing reduced intensity transplantation fromhaploidentical related donors. Bone Marrow Transplantation,2012,47:817-823.
15. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
16. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
17. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
18. Cook MA, Milligan DW, Fegan CD, et al. The impact of donor KIR and patientHLA-C genotypes on outcome following HLA-identical sibling hematopoietic stemcell transplantation for myeloid leukemia. Blood,2004,103:1521-1526.
19. Wongwuttisaroj N, Vejbaesya S, Chongkolwatana V, et al. Analysis of KIR genes inHLA-identical sibling hematopoietic stem cell transplantation in Thai patients withleukemia. J Med Assoc Thai,2012,95:1261-1265.
20. Dou LP, Zheng DH, Wang C, et al. The diversity of KIR gene in Chinese NorthernHan population and the impact of donor KIR and patient HLA genotypes on outcomefollowing HLA-identical sibling allogeneic hematopoietic stem cell transplantation forhematological malignancy in Chinese people. Int J Hematol,2008,87:422-433.
21. Sobecks RM, Ball EJ, Maciejewski JP, et al. Survival of AML patients receivingHLA-matched sibling donor allogeneic bone marrow transplantation correlates withHLA-Cw ligand groups for killer immunoglobulin-like receptors. Bone MarrowTransplantation,2007,39:417-424.
22. U. Kanga, M. Mourya, T. Seth, et al. Role of Killer Immunoglobulin-likeReceptor-Ligand Interactions in Human Leukocyte Antigen–Matched SiblingHematopoietic Stem Cell Transplantation. Transplantation Proceedings,2012,44:919-921.
23. Littera R, Orru N, Vacca A, et al. The role of killer immunoglobulin-like receptorhaplotypes on the outcome of unrelated donor haematopoietic SCT for thalassaemia.Bone Marrow Transplant,2010,45:1618-1624.
24. Gagne K, Brizard G, Gueglio B, et al. Relevance of KIR gene polymorphisms in bonemarrow transplantation outcome. Human Immunology,2002,63:271-280.
25. Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects ofallogeneic NK cells. Journal of Immunology,2004,172:644-650.
26. Farag S, Fehniger T, Ruggeri L, et al. Natural killer cell receptors: new biology andinsights into the graft-versus-leukemia effect. Blood,2002,100:1935-1947.
27. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
28. Martin AM, Kulski JK, Gaudieri S, et al. Comparative genomic analysis, diversity andevolution of two KIR haplotypes A and B. Gene,2004,335:121-131.
29. Ruggeri L, Mancusi A, Capanni M, et al. Donor natural killer cell allorecognition ofmissing self in haploidentical hematopoietic transplantation for acute myeloidleukemia: challenging its predictive value. Blood,2007,110:433-440.
30. Leung W, Iyengar R, Leimig T, et al. Phenotype and function of human natural killercells purifed by using a clinical-scale immunomagnetic method. Cancer ImmunologyImmunotherapy,2005,54:389-394.
31. Bishara A, De Santis D, Witt CC, et al. The benefcial role of inhibitory KIR genes ofHLA class I NK epitopes in haploidentically mismatched stem cell allografts may bemasked by residual donor-alloreactive T cells causing GVHD. Tissue Antigens,2004,63:204-211.
32. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cellreceptor genes leads to superior survival after unrelated transplantation for acutemyelogenous leukemia. Blood,2010,116:2411-2419.
33. Fischer JC, Kobbe G, Enczmann J, et al. The impact of HLA-C matching depends onthe C1/C2KIR ligand status in unrelated hematopoietic stem cell transplantation.Immunogenetics,2012,64:879-885.
34. Peggs KS, Mackinnon S. Cytomegalovirus: the role of CMV post-hematopoietic stemcell transplantation. The International Journal of Biochemistry&Cell Biology,2004,36:695-701.
35. Cook M, Briggs D, Craddock C, Mahendra P, et al. Donor KIR genotype has a majorinfluence on the rate of cytomegalovirus reactivation following T-cell replete stem celltransplantation. Blood,2006,1,107:1230-1232.
36. Wu X, He J, Wu D, et al. KIR and HLA-Cw genotypes of donor-recipient pairsinfluence the rate of CMV reactivation following non-T-cell deleted unrelated donorhematopoietic cell transplantation. Am J Hematol,2009,84:776-777.
37. Zaia JA, Sun JY, Gallez-Hawkins GM, et al. The effect of single and combinedactivating killer immunoglobulin-like receptor genotypes on cytomegalovirus infectionand immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant,2009,15:315-325.
38. Ghislaine M, Gallez-Hawkins, Anne E, et al. Franck, Expression of ActivatingKIR2DS2and KIR2DS4Genes after Hematopoietic Cell Transplantation: Relevanceto Cytomegalovirus Infection Biol Blood Marrow Transplant,2011,17:1662-1672.
39. Chen C, Busson M, Rocha V, et al. Activating KIR genes are associated with CMVreactivation and survival after non-T-cell depleted HLA-identical sibling bone marrowtransplantation for malignant disorders. Bone Marrow Transplant,2006,38:437-444.
40. Stern M, Hadaya K, H nger G, et al. Telomeric rather than centromeric activating KIRgenes protect from cytomegalovirus infection after kidney transplantation. Am JTransplant,2011,11:1302-1307.
1. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
2. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
3. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent anti-leukemic effectorcells after allogeneic bone marrow transplantation in mice. Transplantation,1995,59:1734-1736.
4. Asai O, Longo DL, Tian Z, et al. Suppression of graft-versus-host disease andamplification of graft-versus-tumor effects by activated natural killer cells afterallogeneic bone marrow transplantation. J Clin Invest,1998,101:1835-1842.
5. Cooper MA，Fehniger TA，Turner SC，et al．Human naturalkiler cells：a unique innateimmunoregulatory role for the CD56(bright)subset．Blood,2001,97:3146-3151．
6. Béziat V, Descours B, Parizot C, et al. NK cell terminal differentiation: correlatedstepwise decrease of NKG2A and acquisition of KIRs. PLoS One,2010,6,5: e11966.
7. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
8.鲍晓晶，何军，孙爱宁等．KIR2DS4等位基因在无关全相合异基因造血干细胞移植中的作用．中华血液学杂志,2010,31:726-732.
9. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
10. Jalili A．Dendritic cells and their role in cancer immunotherapy．Iran J Immunol,2007,4:127-144．
11. Sallusto F, A Lanzavecchia. Efficient presentationof soluble antigen by culturedhuman dendritic cells is maintained by granulocyte/macrophage colony-stimulatingfactor plus interleukin4and downregulated by tumor necrosis factor. J Exp Med,1994,179:1109–1118.
12. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
13. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
14. Ferlazzo G, Tsang ML, Moretta L, et al. Human dendritic cells activate resting naturalkiller(NK) cells and are recognized via the NKp30receptor by activated NK cells. JExp Med,2002,195:343-351.
15. PiccioliD, Sbrana S, Melandri E, et al. Contact dependent stimulation and inhibition ofdendritic cells by natural killer cells. J Exp Med,2002,195:335-341.
16. Ljunggren HG, K rre K. In search of the 'missing self': MHC molecules and NK cellrecognition. Immunol Today,1990,11:237-44.
17. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
1. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
2. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
3. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent anti-leukemic effectorcells after allogeneic bone marrow transplantation in mice. Transplantation,1995,59:1734-1736.
4. Asai O, Longo DL, Tian Z, et al. Suppression of graft-versus-host disease andamplification of graft-versus-tumor effects by activated natural killer cells afterallogeneic bone marrow transplantation. J Clin Invest,1998,101:1835-1842.
5. Fehniger TA, Caligiuri MA. Interleukin15: biology and relevance to human disease.Blood,2011,97:14-32.
6. Cooper MA，Fehniger TA，Turner SC，et al．Human naturalkiler cells：a unique innateimmunoregulatory role for the CD56(bright) subset. Blood,2001,97:3146-3151．
7. Smyth MJ, Cretney E, Kershaaw MH, et al. Cytokines in cancer immunity andimmunotherapy. Immunol Rev,2004,202:275-293.
8. Farag SS, Fehniger TA, Ruggeri L et al. Nature kill cell receptor: new biology andinsights into the graft-versus leukemia effect. Blood,2002,15,100:1935-1947.
9. Martin AM, Kulski JK, Gaudieri S, et al. Comparative genomic analysis, diversity andevolution of two KIR haplotypes A and B. Gene,2004,335:121-131.
10. Béziat V, Descours B, Parizot C, et al. NK cell terminal differentiation: correlatedstepwise decrease of NKG2A and acquisition of KIRs. PLoS One,2010,6,5:e11966.
11. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
12. Giebel S, Dziaczkowska J, Czerw T, et al. Sequential recovery of NK cell receptorrepertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant,2010,45:1022-1030.
13. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
14. Peters C. Another step forward towards improved outcome after HLA-haploidenticalstem cell transplantation. Leukemia,2004,18:1769-1771.
15. Siegler U, Kalberer CP, Nowbakht P, et al. Activated natural killer cells from patientswith acute myeloid leukemia are cytotoxic against autologous leukemic blasts inNOD/SCID mice. Leukemia,2005,19:2215-2222.
16. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
17. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
18. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
19. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cellreceptor genes leads to superior survival after unrelated transplantation for acutemyelogenous leukemia. Blood,2010,116:2411-2419.
20. Leung W, Iyengar R, Leung W, et al. Determinants of antileukemia effects ofallogeneic NK cells. J Immunol,2004,172:644-650.
21. Reuss-Borst MA, Klein G, Waller HD, et al. Differential expression of adhesionmolecules in acute leukemia. Leukemia,1995,9:869-874.
22. Romanski A, Bug G, Becker S, Kampfmann M, et al. Mechanisms of resistance tonatural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia. ExpHematol,2005,33:344-352.
23. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host diseaseby inactivation of host antigen-presenting cells. Science,1999,285:412-415.
24. Shilling HG, McQueen KL, Cheng NW, et al. Reconstitution of NK cell receptorrepertoire following HLA-matched hematopoietic cell transplantation. Blood,2003,101:3730-3740.
25. Ruggeri L，Capanni M，Martelli MF，et al. Cellular therapy: exploiting NK cellalloreactivity in transplantation. Curr Opin Hematol,2001,8:355-359.
26. Giebel S，Locatelli F，Lamparelli T，et al. Survival advantage with KIR ligandincompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood,2003,102:814-819.
27. Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory andactivating Killer Ig-Like Receptors(KIR) on high-risk patients with myeloid andlymphoid malignancies undergoing reduced intensity transplantation fromhaploidentical related donors. Bone Marrow Transplantation,2012,47:817-823.
28. Biron CA, Byron KS, Sullivan JL, et al. Severe herpesvirus infections in an adolescentwithout natural killer cells. N Engl J Med,1989,320:1731-1735.
29. Biron CA. Activation and function of natural killer cell responses during viralinfections. Current Opinion in Immunology,1997,9:24-34.
30. Sun JC, Lanier LL. The natural selection of herpesviruses and virus-specific NK Cellreceptors. Viruses,2009,1:362-378.
31. Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell,2010,142:847-856.
32. Kielczewska A, Kim HS, Lanier LL, et al. Critical Residues at the Ly49Natural KillerReceptor’s Homodimer Interface Determine Functional Recognition of m157, aMouse Cytomegalovirus MHC Class I-Like Protein. J Immunol,2007,178:369-377.
33. Chen C, Busson M, Rocha V. Activating KIR genes are associated with CMVreactivation and survival after non-T-cell depleted HLA-identical sibling bone marrowtransplantation for malignant disorders. Bone Marrow Transplantation,2006,38:437-444.
34. Cook M, Briggs D, Craddock C, et al. Donor KIR genotype has a major influence onthe rate of cytomegalovirus reactivation following T-cell replete stem celltransplantation. Blood,2006,107:1230-1232.
35. Zaia JA, Sun JY, Gallez-Hawkins.GM, et al. The effect of single and combinedactivating KIR genotypes on CMV infection and immunity after hematopoietic celltransplantation. Bio Blood Marrow Transplant,2009,15:315-325.
36. Xiaojin Wu，Jun He，Depei Wu，et al. KIR and HLA-Cw genotypes of donor-recipientpairs influence the rate of CMV reactivation following non-T-cell deleted unrelateddonor hematopoietic cell transplantation. American Journal of Hematology,2009,84:776-777.
37. Gallez-Hawkins GM, Franck AE, Li X, et al. Expression of activating KIR2DS2andKIR2DS4genes after hematopoietic cell transplantation: relevance to cytomegalovirusinfection. Biol Blood Marrow Transplant,2011,17:1662-1672.
38. Stern M, Hadaya K, H nger G, et al. Telomeric rather than centromeric activating KIRgenes protect from cytomegalovirus infection after kidney transplantation. Am JTransplant,2011,11:1302-1307.
2. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
3. Farag SS, Fehniger TA, Ruggeri L et al. Nature kill cell receptor: new biology andinsights into the graft-versus leukemia effect. Blood,2002,15,100:1935-1947.
4. Giebel S, Dziaczkowska J, Czerw T, et al. Sequential recovery of NK cell receptorrepertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant,2010,45:1022-1030.
5. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
6. Norman PJ, Abi-Rached L, Gendzekhadze K, et al. Meiotic recombination generatesrich diversity in NK cell receptor genes, alleles, and haplotypes. Genome Res,2009,19:757-769.
7. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
8. Pende D, Marcenaro S, Falco M, et al. Anti-leukemia activity of alloreactive NK cellsin KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation ofthe functional role of activating KIR and redefinition of inhibitory KIR specificity.Blood,2009;113:3119-3129.
9. Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory andactivating Killer Ig-Like Receptors(KIR) on high-risk patients with myeloid andlymphoid malignancies undergoing reduced intensity transplantation fromhaploidentical related donors. Bone Marrow Transplantation,2012,47:817-823.
10. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
11. Giebel S, Loeatelli F, LamParelli T, et al. Survival advantage with KIR ligandincompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood,2003,102:814-819.
12. Miller JS, Cooley S, Parham P, et al. Missing KIR ligands are associated with lessrelapse and inereased graft-versus-host disease (GVHD) following unrelated donorallogeneic HCT. Blood,2007,109:5058-5061.
13. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
14. Cook MA, Milligan DW, Fegan CD, et al. The impact of donor KIR and patientHLA-C genotypes on outcome following HLA-identical sibling hematopoietic stemcell transplantation for myeloid leukemia. Blood,2004,103:1521-1526.
15. Wongwuttisaroj N, Vejbaesya S, Chongkolwatana V, et al. Analysis of KIR genes inHLA-identical sibling hematopoietic stem cell transplantation in Thai patients withleukemia. J Med Assoc Thai,2012,95:1261-1265.
16. Dou LP, Zheng DH, Wang C, et al. The diversity of KIR gene in Chinese NorthernHan population and the impact of donor KIR and patient HLA genotypes on outcomefollowing HLA-identical sibling allogeneic hematopoietic stem cell transplantation forhematological malignancy in Chinese people. Int J Hematol,2008,87:422-433.
17. Sobecks RM, Ball EJ, Maciejewski JP, et al. Survival of AML patients receivingHLA-matched sibling donor allogeneic bone marrow transplantation correlates withHLA-Cw ligand groups for killer immunoglobulin-like receptors. Bone MarrowTransplantation,2007,39:417-424.
18. U. Kanga, M. Mourya, T. Seth, et al. Role of Killer Immunoglobulin-likeReceptor-Ligand Interactions in Human Leukocyte Antigen–Matched SiblingHematopoietic Stem Cell Transplantation. Transplantation Proceedings,2012,44:919-921.
19. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
20. Chen C, Busson M, Rocha V. Activating KIR genes are associated with CMVreactivation and survival after non-T-cell depleted HLA-identical sibling bone marrowtransplantation for malignant disorders. Bone Marrow Transplantation,2006,38:437-444.
21. Cook M, Briggs D, Craddock C, et al. Donor KIR genotype has a major influence onthe rate of cytomegalovirus reactivation following T-cell replete stem celltransplantation. Blood,2006,107:1230-1232.
22. Zaia JA, Sun JY, Gallez-Hawkins GM, et al. The effect of single and combinedactivating KIR genotypes on CMV infection and immunity after hematopoietic celltransplantation. Bio Blood Marrow Transplant,2009,15:315-325.
23. Xiaojin Wu，Jun He，Depei Wu，et al. KIR and HLA-Cw genotypes of donor-recipientpairs influence the rate of CMV reactivation following non-T-cell deleted unrelateddonor hematopoietic cell transplantation. American Journal of Hematology,2009,84:776-777.
24. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant2010,45:1435-1441.
25.鲍晓晶,何军,孙爱宁等. KIR2DS4等位基因在无关全相合异基因造血干细胞移植中的作用.中华血液学杂志,2010,31:726-732.
1. Farag SS, Fehniger TA, Ruggeri L et al. Nature kill cell receptor: new biology andinsights into the graft-versus leukemia effect. Blood,2002,15,100:1935-1947.
2. Béziat V, Descours B, Parizot C, et al. NK cell terminal differentiation: correlatedstepwise decrease of NKG2A and acquisition of KIRs. PLoS One,2010,6,5: e11966.
3. Martin AM, Kulski JK, Gaudieri S, et al. Comparative genomic analysis, diversity andevolution of two KIR haplotypes A and B. Gene,2004,335:121-131.
4. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
5. X Bao, M Wang, H Zhou, et al. Characterization of killer cell immunoglobilin-likereceptor (KIR) genotypes and haplotypes in Chinese Han population. Tissu Antigen,2013,82:327-337.
6. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
7. Norman PJ, Abi-Rached L, Gendzekhadze K, et al. Meiotic recombination generatesrich diversity in NK cell receptor genes, alleles, and haplotypes. Genome Res,2009,19:757-769.
8. Hauch M, Gazzola MV, Small T, et al. Anti-leukemia potential of interleukin-2activated natural killer cells after bone marrow transplantation for chronicmyelogenous leukemia. Blood,1990,75:2250-2262.
9. Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity inHLA-mismatched hematopoietic stem cell transplantation. Blood,1999,94:333-339.
10.鲍晓晶,何军,陈子兴,等．非亲缘性HLA全相合的造血干细胞移植中供者-受者NK细胞KIR受体的研究.中华血液学杂志,2007,28:510-513.
11. McQueen KL, Dorighi KM, Guethlein LA, et al. Donor-Recipient Combinations ofGroup A and B KIR Haplotypes and HLA Class I Ligand Affect the Outcome ofHLA-Matched, Sibling Donor Hematopoietic Cell Transplantation. Hum Immunol,2007,68:309-323.
12. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
13. Gagne K, Brizard G, Gueglio B, et al. Relevance of KIR gene polymorphisms in bonemarrow transplantation outcome. Human Immunology,2002,63:271-280.
14. Ruggeri L, Mancusi A, Capanni M, et al. Donor natural killer cell allorecognition ofmissing self in haploidentical hematopoietic transplantation for acute myeloidleukemia: challenging its predictive value. Blood,2007,110:433-440.
15. Ljunggren HG, K rre K. In search of the 'missing self': MHC molecules and NK cellrecognition. Immunol Today,1990,11:237-244.
16. Giebel S, Dziaczkowska J, Czerw T, et al. Sequential recovery of NK cell receptorrepertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant,2010,45:1022-1030.
17. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
18. Siegler U, Kalberer CP, Nowbakht P, et al. Activated natural killer cells from patientswith acute myeloid leukemia are cytotoxic against autologous leukemic blasts inNOD/SCID mice. Leukemia,2005,19:2215-2222.
19. Bottino C, Castriconi R, Pende D, et al. Identification of PVR (CD155) and Nectin-2(CD112) as cell surface ligands for the human DNAM-1(CD226) activating molecule.J Exp Med,2003,18;198:557-567.
20. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes inresolving hepatitis C virus infection. Science,2004,6,305:872-874.
21. Littera R, Orrù N, Vacca A, et al. The role of killer immunoglobulin-like receptorhaplotypes on the outcome of unrelated donor haematopoietic SCT for thalassaemia.Bone Marrow Transplant,2010,45:1618-1624.
22. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
23. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
24. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cellreceptor genes leads to superior survival after unrelated transplantation for acutemyelogenous leukemia. Blood,2010,116:2411-2419.
25. Stringaris K, Adams S, Uribe M, et al. Donor KIR Genes2DL5A,2DS1and3DS1areassociated with a reduced rate of leukemia relapse after HLA-identical sibling stemcell transplantation for acute myeloid leukemia but not other hematologicmalignancies. Biol Blood Marrow Transplant,2010,16:1257-1264.
1. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matchingcontributes to the success of unrelated donor marrow transplantation. Blood,2007,110:4576-4583.
2. McQueen KL, Dorighi KM, Guethlein LA, et al. Donor-Recipient Combinations ofGroup A and B KIR Haplotypes and HLA Class I Ligand Affect the Outcome ofHLA-Matched, Sibling Donor Hematopoietic Cell Transplantation. Hum Immunol,2007,68:309-323.
3. Giebel S, Locatelli F, Lamparelli T, et al. Survival advantage with KIR ligandincompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood,2003,102:814-819.
4. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
5. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
6. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent anti-leukemic effectorcells after allogeneic bone marrow transplantation in mice. Transplantation,1995,59:1734-1736.
7. Tanaka J, Tutumi Y, Mori A, et al. Sequential analysis of HLA-C specific killer cellinhibitory receptor (CD158b) expressing peripheral blood mononuclear cells duringchronic graft-versus-host disease. Bone Marrow Transplant,2000,26:287-290.
8. Asai O, Longo DL, Tian Z, et al. Suppression of graft-versus-host disease andamplification of graft-versus-tumor effects by activated natural killer cells afterallogeneic bone marrow transplantation. J Clin Invest,1998,101:1835-1842.
9. Hauch M, Gazzola MV, Small T, et al. Anti-leukemia potential of interleukin-2activated natural killer cells after bone marrow transplantation for chronicmyelogenous leukemia. Blood,1990,75:2250-2262.
10. Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity inHLA-mismatched hematopoietic stem cell transplantation. Blood,1999,94:333-339.
11. Marsh SG, Parham P, Dupont B, et al. Killer-cell immunoglobulin-like receptor (KIR)nomenclature report.2002. Tissue Antigens,2003,62:79-86.
12. Hsu KC, Liu XR, Selvakumar A, et al. Killer Ig-like receptor haplotype analysis bygene content: evidence for genomic diversity with a minimum of six basic frameworkhaplotypes, each with multiple subsets. J Immunol,2002,169:5118-5129.
13. Pende D, Marcenaro S, Falco M, et al. Anti-leukemia activity of alloreactive NK cellsin KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation ofthe functional role of activating KIR and redefinition of inhibitory KIR specificity.Blood,2009,113:3119-3129.
14. Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory andactivating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid andlymphoid malignancies undergoing reduced intensity transplantation fromhaploidentical related donors. Bone Marrow Transplantation,2012,47:817-823.
15. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
16. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
17. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
18. Cook MA, Milligan DW, Fegan CD, et al. The impact of donor KIR and patientHLA-C genotypes on outcome following HLA-identical sibling hematopoietic stemcell transplantation for myeloid leukemia. Blood,2004,103:1521-1526.
19. Wongwuttisaroj N, Vejbaesya S, Chongkolwatana V, et al. Analysis of KIR genes inHLA-identical sibling hematopoietic stem cell transplantation in Thai patients withleukemia. J Med Assoc Thai,2012,95:1261-1265.
20. Dou LP, Zheng DH, Wang C, et al. The diversity of KIR gene in Chinese NorthernHan population and the impact of donor KIR and patient HLA genotypes on outcomefollowing HLA-identical sibling allogeneic hematopoietic stem cell transplantation forhematological malignancy in Chinese people. Int J Hematol,2008,87:422-433.
21. Sobecks RM, Ball EJ, Maciejewski JP, et al. Survival of AML patients receivingHLA-matched sibling donor allogeneic bone marrow transplantation correlates withHLA-Cw ligand groups for killer immunoglobulin-like receptors. Bone MarrowTransplantation,2007,39:417-424.
22. U. Kanga, M. Mourya, T. Seth, et al. Role of Killer Immunoglobulin-likeReceptor-Ligand Interactions in Human Leukocyte Antigen–Matched SiblingHematopoietic Stem Cell Transplantation. Transplantation Proceedings,2012,44:919-921.
23. Littera R, Orru N, Vacca A, et al. The role of killer immunoglobulin-like receptorhaplotypes on the outcome of unrelated donor haematopoietic SCT for thalassaemia.Bone Marrow Transplant,2010,45:1618-1624.
24. Gagne K, Brizard G, Gueglio B, et al. Relevance of KIR gene polymorphisms in bonemarrow transplantation outcome. Human Immunology,2002,63:271-280.
25. Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects ofallogeneic NK cells. Journal of Immunology,2004,172:644-650.
26. Farag S, Fehniger T, Ruggeri L, et al. Natural killer cell receptors: new biology andinsights into the graft-versus-leukemia effect. Blood,2002,100:1935-1947.
27. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
28. Martin AM, Kulski JK, Gaudieri S, et al. Comparative genomic analysis, diversity andevolution of two KIR haplotypes A and B. Gene,2004,335:121-131.
29. Ruggeri L, Mancusi A, Capanni M, et al. Donor natural killer cell allorecognition ofmissing self in haploidentical hematopoietic transplantation for acute myeloidleukemia: challenging its predictive value. Blood,2007,110:433-440.
30. Leung W, Iyengar R, Leimig T, et al. Phenotype and function of human natural killercells purifed by using a clinical-scale immunomagnetic method. Cancer ImmunologyImmunotherapy,2005,54:389-394.
31. Bishara A, De Santis D, Witt CC, et al. The benefcial role of inhibitory KIR genes ofHLA class I NK epitopes in haploidentically mismatched stem cell allografts may bemasked by residual donor-alloreactive T cells causing GVHD. Tissue Antigens,2004,63:204-211.
32. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cellreceptor genes leads to superior survival after unrelated transplantation for acutemyelogenous leukemia. Blood,2010,116:2411-2419.
33. Fischer JC, Kobbe G, Enczmann J, et al. The impact of HLA-C matching depends onthe C1/C2KIR ligand status in unrelated hematopoietic stem cell transplantation.Immunogenetics,2012,64:879-885.
34. Peggs KS, Mackinnon S. Cytomegalovirus: the role of CMV post-hematopoietic stemcell transplantation. The International Journal of Biochemistry&Cell Biology,2004,36:695-701.
35. Cook M, Briggs D, Craddock C, Mahendra P, et al. Donor KIR genotype has a majorinfluence on the rate of cytomegalovirus reactivation following T-cell replete stem celltransplantation. Blood,2006,1,107:1230-1232.
36. Wu X, He J, Wu D, et al. KIR and HLA-Cw genotypes of donor-recipient pairsinfluence the rate of CMV reactivation following non-T-cell deleted unrelated donorhematopoietic cell transplantation. Am J Hematol,2009,84:776-777.
37. Zaia JA, Sun JY, Gallez-Hawkins GM, et al. The effect of single and combinedactivating killer immunoglobulin-like receptor genotypes on cytomegalovirus infectionand immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant,2009,15:315-325.
38. Ghislaine M, Gallez-Hawkins, Anne E, et al. Franck, Expression of ActivatingKIR2DS2and KIR2DS4Genes after Hematopoietic Cell Transplantation: Relevanceto Cytomegalovirus Infection Biol Blood Marrow Transplant,2011,17:1662-1672.
39. Chen C, Busson M, Rocha V, et al. Activating KIR genes are associated with CMVreactivation and survival after non-T-cell depleted HLA-identical sibling bone marrowtransplantation for malignant disorders. Bone Marrow Transplant,2006,38:437-444.
40. Stern M, Hadaya K, H nger G, et al. Telomeric rather than centromeric activating KIRgenes protect from cytomegalovirus infection after kidney transplantation. Am JTransplant,2011,11:1302-1307.
1. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
2. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
3. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent anti-leukemic effectorcells after allogeneic bone marrow transplantation in mice. Transplantation,1995,59:1734-1736.
4. Asai O, Longo DL, Tian Z, et al. Suppression of graft-versus-host disease andamplification of graft-versus-tumor effects by activated natural killer cells afterallogeneic bone marrow transplantation. J Clin Invest,1998,101:1835-1842.
5. Cooper MA，Fehniger TA，Turner SC，et al．Human naturalkiler cells：a unique innateimmunoregulatory role for the CD56(bright)subset．Blood,2001,97:3146-3151．
6. Béziat V, Descours B, Parizot C, et al. NK cell terminal differentiation: correlatedstepwise decrease of NKG2A and acquisition of KIRs. PLoS One,2010,6,5: e11966.
7. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
8.鲍晓晶，何军，孙爱宁等．KIR2DS4等位基因在无关全相合异基因造血干细胞移植中的作用．中华血液学杂志,2010,31:726-732.
9. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
10. Jalili A．Dendritic cells and their role in cancer immunotherapy．Iran J Immunol,2007,4:127-144．
11. Sallusto F, A Lanzavecchia. Efficient presentationof soluble antigen by culturedhuman dendritic cells is maintained by granulocyte/macrophage colony-stimulatingfactor plus interleukin4and downregulated by tumor necrosis factor. J Exp Med,1994,179:1109–1118.
12. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
13. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
14. Ferlazzo G, Tsang ML, Moretta L, et al. Human dendritic cells activate resting naturalkiller(NK) cells and are recognized via the NKp30receptor by activated NK cells. JExp Med,2002,195:343-351.
15. PiccioliD, Sbrana S, Melandri E, et al. Contact dependent stimulation and inhibition ofdendritic cells by natural killer cells. J Exp Med,2002,195:335-341.
16. Ljunggren HG, K rre K. In search of the 'missing self': MHC molecules and NK cellrecognition. Immunol Today,1990,11:237-44.
17. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
1. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cellalloreactivity in mismatched hematopoietic transplants. Science,2002,295:2097-2100.
2. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identicalsibling hematopoietic stem-cell transplantation for acute myelogenous leukemiapredicted by KIR and HLA genotypes. Blood,2005,105:4878-4884.
3. Zeis M, Uharek L, Glass B, et al. Allogeneic NK cells as potent anti-leukemic effectorcells after allogeneic bone marrow transplantation in mice. Transplantation,1995,59:1734-1736.
4. Asai O, Longo DL, Tian Z, et al. Suppression of graft-versus-host disease andamplification of graft-versus-tumor effects by activated natural killer cells afterallogeneic bone marrow transplantation. J Clin Invest,1998,101:1835-1842.
5. Fehniger TA, Caligiuri MA. Interleukin15: biology and relevance to human disease.Blood,2011,97:14-32.
6. Cooper MA，Fehniger TA，Turner SC，et al．Human naturalkiler cells：a unique innateimmunoregulatory role for the CD56(bright) subset. Blood,2001,97:3146-3151．
7. Smyth MJ, Cretney E, Kershaaw MH, et al. Cytokines in cancer immunity andimmunotherapy. Immunol Rev,2004,202:275-293.
8. Farag SS, Fehniger TA, Ruggeri L et al. Nature kill cell receptor: new biology andinsights into the graft-versus leukemia effect. Blood,2002,15,100:1935-1947.
9. Martin AM, Kulski JK, Gaudieri S, et al. Comparative genomic analysis, diversity andevolution of two KIR haplotypes A and B. Gene,2004,335:121-131.
10. Béziat V, Descours B, Parizot C, et al. NK cell terminal differentiation: correlatedstepwise decrease of NKG2A and acquisition of KIRs. PLoS One,2010,6,5:e11966.
11. Pyo CW, Guethlein LA, Vu Q, et al. Different patterns of evolution in the centromericand telomeric regions of group A and B haplotypes of the human killer cell Ig-likereceptor locus. PLoS One,2010,5: e15115.
12. Giebel S, Dziaczkowska J, Czerw T, et al. Sequential recovery of NK cell receptorrepertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant,2010,45:1022-1030.
13. Purdy AK, Campbell KS. Natural killer cells and cancer. Regulation by the killer cellIg-like receptors (KIR). Cancer Biol Ther,2009,8:2211-2220.
14. Peters C. Another step forward towards improved outcome after HLA-haploidenticalstem cell transplantation. Leukemia,2004,18:1769-1771.
15. Siegler U, Kalberer CP, Nowbakht P, et al. Activated natural killer cells from patientswith acute myeloid leukemia are cytotoxic against autologous leukemic blasts inNOD/SCID mice. Leukemia,2005,19:2215-2222.
16. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killerimmunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors afternonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol BloodMarrow Transplant,2010,16:533-542.
17. Bao XJ, Hou LH, Sun AN, et al. The impact of KIR2DS4alleles and the expression ofKIR in the development of acute GVHD after unrelated allogeneic hematopoietic SCT.Bone Marrow Transplant,2010,45:1435-1441.
18. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypesimprove relapse-free survival after unrelated hematopoietic cell transplantation foracute myelogenous leukemia. Blood,2009,113:726-732.
19. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cellreceptor genes leads to superior survival after unrelated transplantation for acutemyelogenous leukemia. Blood,2010,116:2411-2419.
20. Leung W, Iyengar R, Leung W, et al. Determinants of antileukemia effects ofallogeneic NK cells. J Immunol,2004,172:644-650.
21. Reuss-Borst MA, Klein G, Waller HD, et al. Differential expression of adhesionmolecules in acute leukemia. Leukemia,1995,9:869-874.
22. Romanski A, Bug G, Becker S, Kampfmann M, et al. Mechanisms of resistance tonatural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia. ExpHematol,2005,33:344-352.
23. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host diseaseby inactivation of host antigen-presenting cells. Science,1999,285:412-415.
24. Shilling HG, McQueen KL, Cheng NW, et al. Reconstitution of NK cell receptorrepertoire following HLA-matched hematopoietic cell transplantation. Blood,2003,101:3730-3740.
25. Ruggeri L，Capanni M，Martelli MF，et al. Cellular therapy: exploiting NK cellalloreactivity in transplantation. Curr Opin Hematol,2001,8:355-359.
26. Giebel S，Locatelli F，Lamparelli T，et al. Survival advantage with KIR ligandincompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood,2003,102:814-819.
27. Chen DF, Prasad VK, Broadwater G, et al. Differential impact of inhibitory andactivating Killer Ig-Like Receptors(KIR) on high-risk patients with myeloid andlymphoid malignancies undergoing reduced intensity transplantation fromhaploidentical related donors. Bone Marrow Transplantation,2012,47:817-823.
28. Biron CA, Byron KS, Sullivan JL, et al. Severe herpesvirus infections in an adolescentwithout natural killer cells. N Engl J Med,1989,320:1731-1735.
29. Biron CA. Activation and function of natural killer cell responses during viralinfections. Current Opinion in Immunology,1997,9:24-34.
30. Sun JC, Lanier LL. The natural selection of herpesviruses and virus-specific NK Cellreceptors. Viruses,2009,1:362-378.
31. Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell,2010,142:847-856.
32. Kielczewska A, Kim HS, Lanier LL, et al. Critical Residues at the Ly49Natural KillerReceptor’s Homodimer Interface Determine Functional Recognition of m157, aMouse Cytomegalovirus MHC Class I-Like Protein. J Immunol,2007,178:369-377.
33. Chen C, Busson M, Rocha V. Activating KIR genes are associated with CMVreactivation and survival after non-T-cell depleted HLA-identical sibling bone marrowtransplantation for malignant disorders. Bone Marrow Transplantation,2006,38:437-444.
34. Cook M, Briggs D, Craddock C, et al. Donor KIR genotype has a major influence onthe rate of cytomegalovirus reactivation following T-cell replete stem celltransplantation. Blood,2006,107:1230-1232.
35. Zaia JA, Sun JY, Gallez-Hawkins.GM, et al. The effect of single and combinedactivating KIR genotypes on CMV infection and immunity after hematopoietic celltransplantation. Bio Blood Marrow Transplant,2009,15:315-325.
36. Xiaojin Wu，Jun He，Depei Wu，et al. KIR and HLA-Cw genotypes of donor-recipientpairs influence the rate of CMV reactivation following non-T-cell deleted unrelateddonor hematopoietic cell transplantation. American Journal of Hematology,2009,84:776-777.
37. Gallez-Hawkins GM, Franck AE, Li X, et al. Expression of activating KIR2DS2andKIR2DS4genes after hematopoietic cell transplantation: relevance to cytomegalovirusinfection. Biol Blood Marrow Transplant,2011,17:1662-1672.
38. Stern M, Hadaya K, H nger G, et al. Telomeric rather than centromeric activating KIRgenes protect from cytomegalovirus infection after kidney transplantation. Am JTransplant,2011,11:1302-1307.