摘要
【目的】
1.研究供者KIR和供受者HLA配体对单倍体造血干细胞移植(HSCT)预后的影响;
2.研究供者KIR和受者HLA配体对同胞HLA相合HSCT预后的影响;
3.探讨异基因造血干细胞移植(allo-HSCT)中移植物和移植后一个月患者外周血NK细胞和T细胞上四种抑制型受体(CD158a、CD158b、NKB1及CD94/NKG2A)的表达与造血重建及急性移植物抗宿主病(aGVHD)的关系;
4.研究同种反应性NK细胞用于小鼠单倍体骨髓移植(BMT)中的抗白血病(GVL)作用;
5.探讨同种反应性NK细胞对小鼠单倍体BMT免疫重建的可能有益作用。
【方法】
1.采用特异性序列引物聚合酶链反应(PCR-SSP)方法进行供者KIR及供受者HLA-Cw基因分型;
2.流式细胞仪检测NK及T细胞上四种抑制型受体的表达;
3.免疫磁珠分选法制备供鼠NK细胞及同种反应性NK细胞;
4.建立C57BL/6×BALB/c(BCF_1)→BALB/c小鼠(荷EL9611红白血病)单倍体BMT模型,观察同种反应性NK细胞的GVL作用;
5.应用C57BL/6×BALB/c(BCF_1)→BALB/c小鼠单倍体BMT模型,观察同种反应性NK细胞对免疫重建的可能影响:胸腺病理组织学观查;流式细胞仪检测外周血CD3e的表达;脾细胞增殖实验;酶联免疫吸附试验(ELISA)测定外周血血清及脾细胞培养上清IL-4、IFN-γ浓度。
【结果】
1.在单倍体HSCT中,供者KIR2DS3、KIR3DS1显著延迟中性粒细胞重建,同时KIR3DS1显著延迟血小板重建;KIR2DS1、KIR2DS3、KIR3DS1显著降低慢性GVHD(cGVHD);受者HLA-Bw4阳性显著增加aGVHD发生率(以上各组与相应组比较,P均＜0.05);GVH方向HLA配体不合组与相合组、KIR受体—HLA配体不合组与相合组比较,造血重建、DFS、复发、TRM没有显著性差别(P均＞0.05)。
2.在同胞HLA相合HSCT中,供者KIR2DS5显著延迟中性粒细胞重建;KIR2DS2显著增加aGVHD和CMV病毒血症的发生率(P均＜0.05);C1纯合组与C1/C2杂合组相比,cGVHD发生率显著降低,而且4例广泛型cGVHD均发生在C1/C2杂合组,同时C1纯合组败血症/肺感染的发生率显著降低(P均＜0.05);KIR受体—HLA配体不合组DFS显著高于相合组[移植后600天DFS分别为(88.89±7.41)%、(53.85±13.83)%,P＜0.05],同时不合组复发率有低于相合组的趋势(P=0.08)。
3.移植物NK细胞上CD158a、NKB1、CD94/NKG2A的表达在Ⅱ～Ⅳ度aGVHD组明显高于0～Ⅰ度aGVHD组;而CD8~+T细胞上CD94/NKG2A的表达在0～Ⅰ度aGVHD组明显高于Ⅱ～Ⅳ度aGVHD组(P均＜0.05)。
4.同种反应性NK细胞显著延长接受单倍体BMT的荷白血病BALB/c小鼠的生存期,降低复发率(与非同种反应性NK细胞组和单纯BMT组比较,P均＜0.05)。
5.同种反应性NK细胞促进单倍体BMT小鼠的外周T细胞免疫重建,体内有效诱导Th1型免疫反应的偏移。
【结论】
1.在单倍体HSCT中,供者激活型KIR2DS3、KIR3DS1延迟造血重建,KIR2DS1、KIR2DS3、KIR3DS1降低cGVHD;受者Bw4增加aGVHD;GVH方向HLA配体是否相合、KIR受体—配体是否相合对造血重建、DFS均无显著影响。
2.在同胞HLA相合HSCT中,供者激活型KIR2DS5延迟造血重建,KIR2DS2增加aGVHD和CMV病毒血症的发生;C1纯合状态降低cGVHD发生率和严重程度,降低感染;KIR受体—HLA配体不合可能降低复发,改善DFS。
3.Allo-HSCT中移植物中NK细胞高表达CD158a、NKB1、CD94/NKG2A时增加Ⅱ-Ⅳ度aGVHD,而CD8+T细胞上高表达CD94/NKG2A降低Ⅱ-Ⅳ度aGVHD。
4.同种反应性NK细胞用于单倍体BMT的荷白血病BALB/c小鼠,延长生存期,降低复发率,具有GVL的作用。
5.同种反应性NK细胞促进单倍体BMT小鼠的外周T细胞免疫重建,体内有效诱导Th1型免疫反应的偏移。
Objective
1. To explore the impact of donor killer immunoglobulin-like receptors(KIR) and donor/recipient HLA ligands on outcome in haploidentical hematopoietic stem cell transplantation(HSCT).
2. To explore the impact of donor KIR and recipient HLA ligands on outcome in HLA-matched, sibling donor HSCT.
3. To investigate the correlation of four types of inhibitory receptors (CD158a, CD158b, NKB1 and CD94/NKG2A) on NK cells and T lymphocytes from grafts and recipients peripheral blood cells 1m after allogeneic HSCT (allo-HSCT) with hematopoietic reconstitution and acute graft-versus-host disease(aGVHD).
4. To study antileukemia effect by alloreactive NK cells mediated in murine undergoing haploidentical bone marrow transplantation(BMT).
5. To investigate the promotion of immune reconstitution of alloreactive NK cells in murine undergoing haploidentical BMT.
Methods
1. Donor KIR and donor/recipient HLA-Cw genotype was determined by PCR -sequence-specific primer analysis(PCR-SSP).
2. Four types of inhibitory receptors on NK cells and T lymphocytes were analyzed the expression by flow cytometry.
3. Murine NK cells and alloreactive NK cells were prepared by immunomagnetic separation.
4. The murine haploidentical BMT model was established by using C57BL/6×BALB/c (BCF_1) mice as donor, and BALB/c mice bearing EL9611 leukemia as recipient, and GVL effect was observed by infusion of grafts with or without alloreactive or non-alloreactive NK cells.
5. The effect of alloreactive NK cells on immune reconstitution was observed in C57BL/6×BALB/c (BCF_1)→BALB/c murine haploidentical BMT model.
Results
1. In haploidentical HSCT, the presence of donor KIR2DS3, KIR3DS1 delayed neutrophil reconstitution, and KIR3DS1 delayed platelet reconstitution. KIR2DS1, KIR2DS3 and KIR3DS1 reduced cGVHD. The presence of recipient HLA-Bw4 increased aGVHD (P<0.05, respectively). Hematopoietic reconstitution, disease-free survival(DFS) and relapse were not significantly different between those with and without HLA ligands incompatibility, and those with and without KIR receptor-HLA ligand incompatibility(P>0.05, respectively).
2. In HLA-matched sibling HSCT, the presence of donor KIR2DS5 delayed neutrophil reconstitution. KIR2DS2 significantly increased aGVHD and CMV(P<0.05). The incidences of cGVHD and septicemia /pneumonia were significantly lower in patients homozygous for group C1 allele than in those heterozygous for group C1/C2 allele(P<0.05). The DFS was significantly higher in patients with KIR receptor-HLA ligand incompatibility than in patients without(P<0.05), and the former group had a lower relapse trend (P=0.08).
3. The percentage of CD158a, NKB1 and CD94/NKG2A expressing on NK cells in grafts was significantly higher in grade II～IV aGVHD group compared with in grade 0~I aGVHD group. The percentage of CD94/NKG2A expressing on CD8-positive T cells in grafts was significantly higher in grade 0～I aGVHD group compared with in grade II～IV aGVHD group( P<0.05, respectively).
4. Alloreactive NK cells significantly prolonged survival of BALB/c mice bearing leukemia that accepted haploidentical BMT and reduced relapse (compared with nonalloreactive NK cells and no NK cells, P<0.05, respectively).
5. Alloreactive NK cells significantly promoted peripheral T cell reconstitution and induced Th1 immune response in vivo in BALB/c mice received haploidentical BMT.
Conclusion
1. In haploidentical HSCT, the presence of donor activating KIR2DS3, KIR3DS1 delays hematopoietic reconstitution. KIR2DS1, KIR2DS3 and KIR3DS1 reduces cGVHD. The presence of recipient Bw4 increases aGVHD.
2. In HLA-matched sibling HSCT, the presence of donor activating KIR2DS5 delays hematopoietic reconstitution. KIR2DS2 increases incidence of aGVHD and CMV viremia. The incidence and severity of cGVHD are significantly reduced in patients homozygous for group C1 allele. KIR receptor-HLA ligand incompatibility may reduce relapse and improve DFS.
3. The higher percentage of CD158a, NKB1 and CD94/NKG2A expressing on NK cells in grafts increases grade II～IV aGVHD. The higher percentage of CD94/NKG2A expressing on CD8-positive T cells reduces grade II～IV aGVHD.
4. Alloreactive NK cells significantly prolong survival of BALB/c mice bearing leukemia that accepted haploidentical BMT , and reduces relapse and has a graft versus leukemia(GVL) role.
5. Alloreactive NK cells significantly promote peripheral T cell reconstitution and induce Th1 immune response in vivo in BALB/c mice received haploidentical BMT.
引文
1. Boyington JC, Brooks AG, Sun PD. Structure of killer cell immunoglobulin-like receptors and their recognition of class I MHC molecules. Immunol Rev, 2001,181: 66-78.
2. Biassoni R, Cantoni C, Falco M, et al. The human leukocyte antigen (HLA)-C-specific"activatory"or"inhibitory"natural killer cell receptors display highly homologous extracellular domains but difer in their tran smembrane and intracytoplasmic portions. J Exp Med, 1996, 183: 645-650.
3. Parham P, McQueen KL. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nat Rev Immunol, 2003, 3: 108-122.
4. Hsu KC, Dupont B. Natural killer cell receptors: regulating innate immune responses to hematologic malignancy. Semin Hematol, 2005, 42: 91-103.
5. Boyington JC, Motyka SA, S chuck P, et al. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature,2000, 405: 537-543.
6. Uhrberg M, Valiante NM , Shum BP, et al. Human diversity in killer cell inhibitory receptor genes. Immunity, 1997, 7: 753-763.
7. Litwin V, Gumperz J, Parham P, et al. NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA·B molecules. J Exp Med, 1994,180: 537-543.
8. Farag S, Fehniger T, Ruggeri L, et al. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood, 2002, 100: 1935-1947.
9. Chen C, Busson M, Rocha V, et al. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplantation, 2006, 38: 437-444.
10. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, 2002, 295 :2097-2100.
11. Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects of allogeneicNK cells.J Immunol, 2004, 172: 644-650.
12. Bishara A, De Santis D, Witt CC, et al. The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD.Tissue Antigens., 2004, 63: 204-211.
13. Miller JS, Cooley S, Parham P, et al. Missing KIR-ligands is associated with less relapse and increased graft versus host disease (GVHD) following unrelated donor allogeneic HCT. Blood, 2007, 109: 5058-5061.
14. Davies SM, Ruggieri L, DeFor T, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood, 2002, 100:3825-3827.
15. Lowe EJ, Turner V, Handgretinger R, et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol, 2003, 123: 323-326.
16. Bornhauser M, Schwerdtfeger R, Martin H, et al. Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors.Blood, 2005, 103: 2860-1.
17. Giebel S, Locatelli F, Lamparelli T, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood, 2003, 102: 814-819.
18. Beelen DW, Ottinger HD, Ferencik S, et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood, 2005, 105: 2594-2600.
19. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood, 2005, 105: 4878-4884.
20. Cook MA, Millingan D, Fegan CD, et al. The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia. Blood, 2004, 103: 1521-1526.
21. Sobecks RM, Ball EJ, Maciejewski JP, 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, 2007, 39: 417-424.
22. Verheyden S, Schots R, Duquet W, et al. A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation.Leukemia., 2005, 19: 1446-1451.
23. Schellekens J, Rozemuller EH, Petersen EJ, et al. Activating KIRs exert a crucial role on relapse and overall survival after HLA-identical sibling transplantation.Mol Immunol, 2008, 45: 2255-2261.
24. Cooley S, McCullar V, Wangen R, et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood, 2005, 106: 4370-4376.
25. Yabe T, Matsuo K, Hirayasu K, et al. Donor killer immunoglobulin-like receptor (KIR) genotype- patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantation.Biol Blood Marrow Transplant., 2008, 14: 75-87.
26. McQueen KL, Dorighi KM, Guethlein LA, et al. Donor-recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation. Hum Immunol.,2007, 68: 309-323.
27. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science, 2004, 305: 872-874.
28. Fischer JC, OttingerH, Ferencik S, etal. Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor. J Immunol, 2007, 178:3918-3923.
29. Ruggeri L, Mancusi A, Capanni M, et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood, 2007, 110: 433-440.
30. Gagne K, Brizard G, Gueglio B, et al. Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum. Immunol, 2002, 63: 271-280.
31.Sun JY, Gaidulis L, Dagis A, et al. Killer Ig-like receptor (KIR) compatibility plays a role in the prevalence of acute GVHD in unrelated hematopoietic cell transplants for AML. Bone Marrow Transplant, 2005, 36: 525-530.
32. Kim HJ, Choi Y, Min WS, et al. The activating killer cell immunoglobulin-like receptors as important determinants of acute graft-versus host disease in hematopoietic stem cell transplantation for acute myelogenous leukemia.Transplantation., 2007, 84: 1082-1091.
33. De Santis D, Bishara A, Witt CS, et al. Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants. Tissue Antigens, 2005, 65: 519-528.
34. Arase H, Mocarski ES, Campbell AE, et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science, 2002, 296: 1323-1326.
35. Cook M, Briggs D, Craddock C, et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood., 2006, 107: 1230-1232.
36. Martin MP, Gao X, Lee JH, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet, 2002, 31: 429-434.
37. Yen JH, Moore BE, NakajimaT, et al. Major histocompatibility complex class Irecognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med,2001, 193: 1159-1167.
38. Momot T, Koch S , Hunzelmann N, et al. Association of killer cell immunoglobulinlike receptors with scleroderma. Arthritis Rheum, 2004, 50:1561-1565.
39. Long EO, Barber DF, Burshtyn DN, et al. Inhibition of natural killer cell activation signal by killer cell immunoglobulin-like receptors (CD 158). Immunol Rev,2001,181:223-233.
40.Lundqvist A,McCoy JP,Samsel L,et al.Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors.Blood.,2007,109:3603-3606.
41.Burchielli E,Ruggeri L,Hafen K,et al.NK cell conditioning to T cell-replete mismatched bone marrow transplantation protects thymic structure and function [abstract].Bone Marrow Transplant,2004,33:S56.
42.何讳,王荷花,王玫等.同种反应性自然杀伤细胞在小鼠主要组织相容性复合物半相合骨髓移植中的作用.中华血液学杂志,2006,27(2):82-86.
43.丁顺利,褚建新,赵钧铭等.可移植性BALB/c小鼠红白血病模型的建立及其生物学特性.中华血液学杂志,1998,19(12):638-641.
44.Murphy W,Koh CY,Raziuddin A,et al.Immunobiology of natural killer cells and bone marrow transplantation:merging of basic and preclinical studies.Immunol Rev,2001,181:279-289.
45.Jacques Z,Vassilios I,Werner H.H-2D ligand expression by Ly49A natural killer (NK) cells precludes ligand uptake from environmental cells:implications for NK cell function.J Exp Med,2001,194:1531-1539.
46.Johansson S,Johansson M,Rosmaraki E,et al.Natural killer cell education in mice with single or multiple major histocompatibility complex class Ⅰ molecules.J Exp Med,2005,201:1145-1155.
47.Ruggeri L,Perruccio K,Montagnoli C,et al.NK cell conditioning to T cell-replete mismatched BMT confers immediate responsiveness to infectious challenges[abstract].Bone Marrow Transplant,2004,33:S18.
1. Bignon JD, Gagne K. KIR matching in hematopoietic stem cell transplantation.Curr Opin Immunol, 2005 , 17:553-559.
2. Parham P, McQueen KL. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nat Rev Immunol., 2003 ,3:108-122.
3. Pando MJ, Gardiner CM, Gleimer M, et al. The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1. J Immunol.,2003,171:6640-6649.
4. Trompeter HI, Gomez-Lozano N, Santourlidis S, et al.Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3. J Immunol., 2005, 174:4135-4143.
5. Chan HW, Miller JS, Moore MB, et al. Epigenetic control of highly homologous killer Ig-like receptor gene alleles. J Immunol., 2005 , 175:5966-5974.
6. Santourlidis S, Trompeter HI, Weinhold S, et al. Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells. J Immunol, 2002, 169:4253-4261.
7. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, 2002, 295:2097-2100.
8. Bonorino P, Leroy V, Dufeu-Duchesne T, et al. Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C. Hepatology, 2007 , 46: 1375-1386.
9. Vivier E, Anfossi N. Inhibitory NK-cell receptors on T cells: witness of the past,actors of the future. Nat Rev Immunol. 2004, 4: 190-198.
10. Ruggeri L, Mancusi A, Burchielli E, et al Natural killer cell recognition of missing self and haploidentical hematopoietic transplantation. Semin Cancer Biol,2006,16:404-411.
11. Rugged L, Mancusi A, Capanni M, et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood, 2007, 110(1): 433-440.
12. Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol, 2004, 172:644-650.
13. Bishara A, De Santis D, Witt CC, et al. The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD.Tissue Antigens., 2004 , 63:204-211.
14. Nguyen S, Dhedin N, Vernant JR NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood, 2005, 105:4135-4142.
15. Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood , 2005,105:4878-4884.
16. Cook MA, Millingan D, Fegan CD, et al.The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia. Blood, 2004, 103:1521-1526.
17. Sobecks RM, Ball EJ, Maciejewski JP,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, 2007,39:417-424.
18. Verheyden S, Schots R, Duquet W ,et al. A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation. Leukemia.,2005,19:1446-1451.
19. Keller MD, Chen DF, Condron SA, et al.The Effect of Natural Killer Cell Killer Ig-Like Receptor Alloreactivity on the Outcome of Bone Marrow Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID).J Clin Immunol,2007,27:109-116.
20. Chen C, Busson M, Rocha V.et al. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplant.2006,38:437-444.
21. Giebel S, Locatelli F, Lamparelli T,et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors.Blood, 2003,102:814-819.
22. Morishima Y, Yabe T, Inoko H. Clinical significance of killer Ig-like receptor(KIR) on acute GVHD, rejection and leukemia relapse in patients transplanted non-T cell depleted marrow from unrelated donors; roles of inhibitory KIR epitope matching and activating KIR genotype. Blood, 2003,102:526a.
23. Elmaagacli AH, Ottinger H, Koldehoff M. Reduced risk of molecular and haematological relapse in patients with CML after KIRmismatched hematopoietic stem cell transplantation. Bone Marrow Transpl, 2004, 33:S59.
24. BeelenDW, Ottinger HD, Ferencik S, et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood, 2005,105:2594-2600.
25. Cooley S, McCullar V, Wangen R, et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood, 2005, 106:4370-4376.
26. Davies SM, Ruggieri L, DeFor T, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood,2002,100:3825-3827.
27. Lowe EJ, Turner V, Handgretinger R, et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol, 2003, 123:323-326.
28. Bornhauser M, Schwerdtfeger R, Martin H, et al. Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood ,2004, 103:2860-2861.
29. Schaffer M, Malmberg KJ, Ringden O, et al. Increased infection-related mortality in KIR-ligand-mismatched unrelated allogeneic hematopoietic stem-cell transplantation. Transplantation, 2004, 78:1081-1085.
30. Shilling HG, McQueen KL, Cheng NW, et al. Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood,2003,101:3730-3740.
31. Miller JS, Cooley S, Parham P, et al. Missing KIR-ligands is associated with less relapse and increased graft versus host disease (GVHD) following unrelated donor allogeneic HCT. Blood, 2007,109: 5058-5061.
32. Giebel S, Nowak I, Wojnar J,et al.Impact of activating killer immunoglobulin-like receptor genotype on outcome of unrelated donor-hematopoietic cell transplantation.Transplant Proc, 2006, 38:287-291.
33. Denis L, Gagne K, Gueglio B,et al. NK-KIR Transcript Kinetics Correlate With Acute Graft-Versus-Host Disease Occurrence After Allogeneic Bone Marrow Transplantation. Human Immunology, 2005,66: 447-459.
34. Fischer JC, Ottinger H, Ferencik S, et al.Relevance of C1 and C2 Epitopes for Hemopoietic Stem Cell Transplantation: Role for Sequential Acquisition of HLA-C-Specific Inhibitory Killer Ig-Like Receptor. J Immunol, 2007, 178:3918-3923.
35. Cook M, Briggs D, Craddock C,et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood, 2006,107:1230-1232.
36. Arase H , Mocarski ES , Campbell AE , et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science, 2002,296: 1323-1326.
37. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in cancer patients. Blood,2005, 105:3051-3057.
38. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005, 106:376-383.
39. Lundqvist A, McCoy JP, Samsel L, et al. Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors. Blood., 2007, 109(8): 3603-3606.
40. Yabe T, Matsuo K, Hirayasu K, et al. Donor killer immunoglobulin-like receptor (KIR) genotype- patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantation.Biol Blood Marrow Transplant., 2008, 14(1): 75-87.
41. McQueen KL, Dorighi KM, Guethlein LA, et al. Donor-recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation. Hum Immunol.,2007, 68(5): 309-23.
42. Schellekens J, Rozemuller EH, Petersen EJ, et al. Activating KIRs exert a crucial role on relapse and overall survival after HLA-identical sibling transplantation.Mol Immunol., 2008, 45(8): 2255-2261.