供者KIR和受者HLA遗传背景与亲缘全相合HSCT预后的关系
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摘要
异基因造血干细胞移植(alloHSCT)是治疗恶性血液病的有效手段,aGVHD是术后主要并发症和死亡的重要原因之一。选择HLA配型相同的供者是减轻aGVHD、保证alloHSCT成功的重要前提。大约有70%的患者无HLA相同的同胞供者,须从血缘无关的志愿者中寻找供者。中国是多民族国家,HLA分布复杂,虽然对HLA-ABDR基因频率及单体型研究较为深入,有关HLA-Cw基因多态性及其与HLA-ABDR之间的连锁不平衡分析的研究却明显滞后。近年来发现HLA-Cw是杀伤细胞免疫球蛋白样受体(KIR)的配体,在免疫调节中发挥作用,对HLA-Cw的研究日益受到重视。因此调查不同人群HLA Ⅱ、Ⅱ类基因频率,分析HLA等位基因多态性及连锁不平衡规律,为HSCT供者选择提供信息,不但具有科学价值,而且具有现实意义。
采用HSCT治疗白血病等恶性血液病时,所面临的另一重要问题是疾病的复发。一定程度的aGVHD有助于引发移植物抗白血病反应(GVLR),降低复发。理想的HSCT应当致力于达到这样的目标:减轻或避免aGVHD的发生,同时保留和促进GVLR。杀伤细胞免疫球蛋白样受体(K/R)的发现为这一目标提供了基础。KIR表达在NK细胞和部分T细胞表面,与HLA Ⅰ类分子结合,传导活化或抑制信号,从而调节NK细胞和T细胞的活性。生理情况下抑制性KIR与自身HLA Ⅰ类分子结合,产生的抑制信号占据主导地位,有效地抑制NK细胞对正常组织细胞杀伤功能,从而识别“自我”。病毒感染细胞和肿瘤细胞表面HLA Ⅰ类分子表达减少、缺失,解除对NK细胞的抑制信号,使活化性
Allogenetic hematopoietic stem cell transplantation (alloHSCT) is a valuable therapy for malignant haematological diseases. One of the major challenges to successful outcome after alloHSCT is the need to overcome acute graft verse host disease (aGVHD). Effort to decrease the risk of aGVHD require optimal donor matching for human leukocyte antigen (HLA). Approximately 70 percent of the patients have no HLA-identical related donor, whom needs to be selected in unrelated volunteers. China is a multinational country and HLA distribution in it is complicated. Although studies of polymorphism and hyplotype character in HLA-ABDR have been carried thoroughly, research in HLA-Cw needs to be enhanced as it has been proved being the ligand of killer cell immunoglobulin -like receptor (KIR) and may regulate immune response. It possesses both scientific and practical importance to investigate HLA allele frequencies, polymorphism as well as their linkage disequilibrium in different Chinese population so as to provide information for donor selection.Another major challenge alloHSCT faced is the relapse of malignant diseases. It
has been observed in clinical that some degree of aGVHD may be helpful in triggering graft verse leukemia reaction (GVLR). The ideal aim of alloHSCT is to lessen or avoid aGVHD while reserve and promote GVLR. Killer cell immunoglobulin -like receptor (KIR) makes it possible to approach the ideal aim. KIRs are members of the immunoglobulin superfamily expressed on the surface of natural killer (NK) cells and a subset of T cells. The function of NK-cell is regulated through the combination of KIR and HLA class I molecules distributed on target cells so that an inhibitory or active signal can be delivered. In normal inhibitory KIR binding with HLA class I is predominant and NK killing of autologous cells is prevented. When faced with mismatched allogeneic targets, NK cells sense the missing expression of self-HLA class I molecules and mediate alloreactions. In transplants between HLA non-identical donors and recipients, it has been observed that donor NK cells encountering recipient target cells lacking an corresponding HLA class I allele can mediate anti-leukemic effects in myeloid leukemias, if the class I mismatch predicts lack of ligand for donor inhibitory KIR. These anti-leukemic effects include lower rates for relapse, graft failure, and GVHD, ultimately translating into a higher overall survival (OS). Possibly, donor KIR and recipient HLA incompatibility may provide a new approach to improving alloHSCT outcome and immunomodulation therapy. It is known that the KIR genes and HLA genes are located on different human chromosome, and expressed separately. It is possible that KIR and HLA incompatibility appears between HLA-identical sibling donors and recipients. About 70 percent of alloHSCT were performed between HLA-identical sibling donors and recipients, however, it is still unclear about the relationship between the genetic background of donor KIR-recipient HLA and the outcome of it.This research includes three parts, HLA-A, B, Cw and DRB1 allele frequencies were detected, polymorphism and haplotypes of HLA class I and II were analyzed in Guangdong Han population in the first part so as to supply data for donor selection. In the second part HLA-Cw allele frequencies were surveyed and its allele polymorphism characteristics were explored in Guangdong Han population and the results were compared with those of some other populations. The recognition
character between HLA-Cw and KIR in Guangdong Han population was analyzed. In the third part of this context a retrospective study was carried in order to analyze the outcomes of patients with various hematologic malignancies who received non T-cell depleted transplants from HLA-identical sibling donors, grouped according to lack or presence of recipient HLA ligand for donor inhibitory KIR. The results may offer molecular evidence in optimal donor selection directed by inheritance and may be advisory in clinical therapy.Methods1.Analysis of HLA class I and II polymorphism and haplotypes in Guangdong Han population160 cases of healthy donors from Guangdong Han population, all performed HLA type during 1996 to 2000 in Guangzhou tissue typing centre, Guangzhou blood centre, were studied. Venous blood was gathered and anticoagulated with ACD-B, DNA was extracted with QIAamp DNA extracting kit. Sequence specific oligonucleotide probes(SSOP, Dynal) and/or sequence specific primer polymerase chain reproduction (PCR-SSP, Biotest) was adopted to type HLA-A, B, Cw and DR. HLA-A, B, Cw and DR allele frequencies were calculated and linkage disequilibrium (LD) and relative linkage disequilibrium (RLD) were computed by serial analysis of gene expression (SAGE) software.2. The gene frequency of HLA-Cw in Guangdong Han population and its significance analysisVenous blood collection, DNA extracting and HLA-Cw genotyping were the same with part one. Hardy-Weinberg equilibrium test were performed using SAGE. Chi-square test was used in comparison of allele frequencies in different populations and t-test was used in comparison of allele frequencies between HLA-C1 and HLA-C2 group by SPSS 10.0.3. The relationship between genetic background of donor KIR-recipient HLA and the outcomes in HLA-identical sibling hematopoietic stem cell transplantationFifty-nine transplants performed between 1996 and 2000 were analyzed. Patients
with various hematologic malignancies received non T-cell depleted transplants from HLA- A, B, Cw, DR. identical sibling donors were observed and clinical data were collected. Venous blood collection, DNA extracting and HLA genotyping were the same with part one. KIR genotyping was realized by SSP-PCR. Various grouped definition were listed as bellow:HLA-KIR model: the inhibitory KIR with identified HLA ligands are KIR2DL2 and KIR2DL3, which recognize the HLA-C group 1-related alleles such as HLA-Cw 01,03,07,08 characterized by an asparagine residue at position 80 of the a-1 helix (HLA-C^"80); The inhibitory KIR with identified HLA ligand is KIR2DL1, which recognizes the HLA-C group 2-related alleles such as HLA-Cw*02,04,05,06 characterized by a lysine residue at position 80 (HLA-CLys8°); and KIR3DL1, which recognizes the HLA-BBw4 alleles.HLA-KIR group: KIR ligand absence ("missing KIR ligand") is defined as the absence of one or more recipient HLA epitopes for the identified donor inhibitory KIR. KIR ligand presence is defined as the presence of all the recipient HLA epitopes for the identified donor inhibitory KIR. KIR ligand absence is further classified as C2, Bw4,C2-Bw4 absence according to the absence of specific recipient HLA-ligand C2, Bw4,C2-Bw4 respectively.KIR-HLA match refers to the presence of at least one recipient HLA epitopes for the identified donor inhibitory KIR. KIR-HLA mismatch refers to the absence of all the recipient HLA epitopes for the identified donor inhibitory KIR. KIR-HLA matched group is further classified as Cl, Bw4, Cl-Bw4 and Cl-C2-Bw4 subgroup according to the presence of specific recipient HLA-ligand Cl, Bw4, Cl-Bw4 and Cl-C2-Bw4 C2 respectively.The log-rank statistic of Kaplan-Meier method was used to evaluate the univariate effects on overall survival and disease-free survival. Chi-square test was used in comparison of occurrence of aGVHD, 5 -year relapse, treatment related mortality and the incidence of infections.
Results1. Analysis of HLA class I, II polymorphism and haplotypes in Guangdong Han population14 HLA-A, 23 B, 11 Cw and 13 DRB1 alleles were obtained, Among which the following allele had higher frequency distribution: HLA-A* 11 (0.3292), A*02 (0.2929), A*24 (0.1340), A*33 (0.1268), HLA-B*60 (0.1268), B*75 (0.1197), B*58 (0.1161), B*46 (0.1197), HLA-Cw*03 (0.2580), Cw*07 (0.2016), Cw *01 (0.1708) Cw*08 (0.1056), HLA-DRB1*12 (0.1708), DRB1*14 (0.1197), DRB1*O9 (0.1197) .A total of 9 HLA-A-B, 20 Cw-B, 7 A-Cw, and 8 A-DRB1, 9 B-DRB1, 10 Cw-DRBl haplotypes were found. List as bellow were the haplotypes with very strong linkage disequilibrium (LD): A*02-B*46, A*33-B*58, B*13-Cw*03, B*46-Cw*01, B*51-Cw*14, B*58-Cw*03, B*75-Cw*08, A*02-Cw*01, A*33-Cw*03,A*33-DRBl*17, B*58-DRB1*17, Cw*03-DRBl*17, CwO8-DRBl*122. The gene frequency of HLA-Cw in Guangdong Han population and its significance analysis2.1 The allele frequencies of HLA-Cw*03, 07, 01, 08, 14, 04, 15, 12, 06, 05, 16 were 0.2580, 0.1887,0.1732, 0.1071, 0.0654, 0.0587, 0.0453, 0.0387, 0.0322,0.0127, 0.0032 respectively. It was tested that HLA-Cw in Guangdong Han population was shown to be in Hardy-Weinberg equilibrium (x2=60.35, u=54, P>0.1).2.2 The Cw*06 allele frequency in Guangdong Han population was only 0.0322, much lower than that in Shanghai Han population (P<0.001). The Japanese Cw* 12, 14 gene frequencies were higher than that in Guangdong Han population (P<0.00l). The Cw*01, 03, 08, 14 allele distribution were higher ,while the Cw* *16 frequency was lower in Guangdong Han population than that in European and African. The allele frequencies of Cw*05, 06, 07 in European and Cw*02, 04, 17 in African are higher than that in Guangdong Hanpopulation respectively(P<0.001).2.3 There was a significant difference in allele frequencies between HLA-C1 group (0.8310) and HLA-Cw2 group (0.1399) in Guangdong Han population
3. The relationship between genetic background of donor KIR-recipient HLA and the outcomes in HLA-identical sibling hematopoietic stem cell transplantationIncidence of grade II -IV aGVHD was lower in patients with KIR-HLA match than that in patients with KIR-HLA mismatch. Incidence of grade II -IV aGVHD and fungus infection were lower in Bw4 matched group than that in Bw4 mismatched group. Incidence of grade II -IV aGVHD was lower in patients of Cl-Bw4 subgroup than that in CK Bw4> Cl-C2-Bw4 subgroups. Over all survival in patients of Cl-C2-Bw4 subgroup was higher than that in Cl, Bw4 or Cl-Bw4 subgroups. Fungus infection ratio was higher in patients of Cl subgroup than that in other subgroups. In myeloid disease, patients with Bw4 match had lower incidence of grade II - IV aGVHD and fungus infection when compared with Bw4 mismatched patients, and patients with C2 match had higher overall survival and disease free survival simultaneously when comparing with C2 mismatched patients.Conclusionsl.HLA class I and II alleles in Guangdong Han population have richer polymorphisms. The haplotype distribution possesses territory characteristic.2.It is easier to select a suitable donor in Guangdong Han population for some patients carrying HLA hyplorypes with strong linkage disequilibrium such as A*02-B*46> B*46-Cw*0K A*02-Cw*01> A*33-DRB1*17, B*58- DRBl*^ Cw*03-DRBl*17 and so on .3. HLA-Cw allele in Guangdong Han population is observed through Hardy-Weinberg equilibrium test being in genetic equilibrium. It has richer polymorphisms and character.4.HLA-C1 gene is predominant compared with HLA-C2 gene in Guangdong Han population.5.Donor KIR-recipient HLA genetic background is related with the outcome in HLA-identical sibling HSCT. Donor selection referring to Bw4 or C2 match may
decrease the incidence of aGVHD or improving the OS and DFS accordingly in patients. Selecting Bw4 matched donor may decrease the incidence of fungus infection, but selecting only Cl matched donor may increase the incidence of fungus infection.
采用HSCT治疗白血病等恶性血液病时,所面临的另一重要问题是疾病的复发。一定程度的aGVHD有助于引发移植物抗白血病反应(GVLR),降低复发。理想的HSCT应当致力于达到这样的目标:减轻或避免aGVHD的发生,同时保留和促进GVLR。杀伤细胞免疫球蛋白样受体(K/R)的发现为这一目标提供了基础。KIR表达在NK细胞和部分T细胞表面,与HLA Ⅰ类分子结合,传导活化或抑制信号,从而调节NK细胞和T细胞的活性。生理情况下抑制性KIR与自身HLA Ⅰ类分子结合,产生的抑制信号占据主导地位,有效地抑制NK细胞对正常组织细胞杀伤功能,从而识别“自我”。病毒感染细胞和肿瘤细胞表面HLA Ⅰ类分子表达减少、缺失,解除对NK细胞的抑制信号,使活化性
Allogenetic hematopoietic stem cell transplantation (alloHSCT) is a valuable therapy for malignant haematological diseases. One of the major challenges to successful outcome after alloHSCT is the need to overcome acute graft verse host disease (aGVHD). Effort to decrease the risk of aGVHD require optimal donor matching for human leukocyte antigen (HLA). Approximately 70 percent of the patients have no HLA-identical related donor, whom needs to be selected in unrelated volunteers. China is a multinational country and HLA distribution in it is complicated. Although studies of polymorphism and hyplotype character in HLA-ABDR have been carried thoroughly, research in HLA-Cw needs to be enhanced as it has been proved being the ligand of killer cell immunoglobulin -like receptor (KIR) and may regulate immune response. It possesses both scientific and practical importance to investigate HLA allele frequencies, polymorphism as well as their linkage disequilibrium in different Chinese population so as to provide information for donor selection.Another major challenge alloHSCT faced is the relapse of malignant diseases. It
has been observed in clinical that some degree of aGVHD may be helpful in triggering graft verse leukemia reaction (GVLR). The ideal aim of alloHSCT is to lessen or avoid aGVHD while reserve and promote GVLR. Killer cell immunoglobulin -like receptor (KIR) makes it possible to approach the ideal aim. KIRs are members of the immunoglobulin superfamily expressed on the surface of natural killer (NK) cells and a subset of T cells. The function of NK-cell is regulated through the combination of KIR and HLA class I molecules distributed on target cells so that an inhibitory or active signal can be delivered. In normal inhibitory KIR binding with HLA class I is predominant and NK killing of autologous cells is prevented. When faced with mismatched allogeneic targets, NK cells sense the missing expression of self-HLA class I molecules and mediate alloreactions. In transplants between HLA non-identical donors and recipients, it has been observed that donor NK cells encountering recipient target cells lacking an corresponding HLA class I allele can mediate anti-leukemic effects in myeloid leukemias, if the class I mismatch predicts lack of ligand for donor inhibitory KIR. These anti-leukemic effects include lower rates for relapse, graft failure, and GVHD, ultimately translating into a higher overall survival (OS). Possibly, donor KIR and recipient HLA incompatibility may provide a new approach to improving alloHSCT outcome and immunomodulation therapy. It is known that the KIR genes and HLA genes are located on different human chromosome, and expressed separately. It is possible that KIR and HLA incompatibility appears between HLA-identical sibling donors and recipients. About 70 percent of alloHSCT were performed between HLA-identical sibling donors and recipients, however, it is still unclear about the relationship between the genetic background of donor KIR-recipient HLA and the outcome of it.This research includes three parts, HLA-A, B, Cw and DRB1 allele frequencies were detected, polymorphism and haplotypes of HLA class I and II were analyzed in Guangdong Han population in the first part so as to supply data for donor selection. In the second part HLA-Cw allele frequencies were surveyed and its allele polymorphism characteristics were explored in Guangdong Han population and the results were compared with those of some other populations. The recognition
character between HLA-Cw and KIR in Guangdong Han population was analyzed. In the third part of this context a retrospective study was carried in order to analyze the outcomes of patients with various hematologic malignancies who received non T-cell depleted transplants from HLA-identical sibling donors, grouped according to lack or presence of recipient HLA ligand for donor inhibitory KIR. The results may offer molecular evidence in optimal donor selection directed by inheritance and may be advisory in clinical therapy.Methods1.Analysis of HLA class I and II polymorphism and haplotypes in Guangdong Han population160 cases of healthy donors from Guangdong Han population, all performed HLA type during 1996 to 2000 in Guangzhou tissue typing centre, Guangzhou blood centre, were studied. Venous blood was gathered and anticoagulated with ACD-B, DNA was extracted with QIAamp DNA extracting kit. Sequence specific oligonucleotide probes(SSOP, Dynal) and/or sequence specific primer polymerase chain reproduction (PCR-SSP, Biotest) was adopted to type HLA-A, B, Cw and DR. HLA-A, B, Cw and DR allele frequencies were calculated and linkage disequilibrium (LD) and relative linkage disequilibrium (RLD) were computed by serial analysis of gene expression (SAGE) software.2. The gene frequency of HLA-Cw in Guangdong Han population and its significance analysisVenous blood collection, DNA extracting and HLA-Cw genotyping were the same with part one. Hardy-Weinberg equilibrium test were performed using SAGE. Chi-square test was used in comparison of allele frequencies in different populations and t-test was used in comparison of allele frequencies between HLA-C1 and HLA-C2 group by SPSS 10.0.3. The relationship between genetic background of donor KIR-recipient HLA and the outcomes in HLA-identical sibling hematopoietic stem cell transplantationFifty-nine transplants performed between 1996 and 2000 were analyzed. Patients
with various hematologic malignancies received non T-cell depleted transplants from HLA- A, B, Cw, DR. identical sibling donors were observed and clinical data were collected. Venous blood collection, DNA extracting and HLA genotyping were the same with part one. KIR genotyping was realized by SSP-PCR. Various grouped definition were listed as bellow:HLA-KIR model: the inhibitory KIR with identified HLA ligands are KIR2DL2 and KIR2DL3, which recognize the HLA-C group 1-related alleles such as HLA-Cw 01,03,07,08 characterized by an asparagine residue at position 80 of the a-1 helix (HLA-C^"80); The inhibitory KIR with identified HLA ligand is KIR2DL1, which recognizes the HLA-C group 2-related alleles such as HLA-Cw*02,04,05,06 characterized by a lysine residue at position 80 (HLA-CLys8°); and KIR3DL1, which recognizes the HLA-BBw4 alleles.HLA-KIR group: KIR ligand absence ("missing KIR ligand") is defined as the absence of one or more recipient HLA epitopes for the identified donor inhibitory KIR. KIR ligand presence is defined as the presence of all the recipient HLA epitopes for the identified donor inhibitory KIR. KIR ligand absence is further classified as C2, Bw4,C2-Bw4 absence according to the absence of specific recipient HLA-ligand C2, Bw4,C2-Bw4 respectively.KIR-HLA match refers to the presence of at least one recipient HLA epitopes for the identified donor inhibitory KIR. KIR-HLA mismatch refers to the absence of all the recipient HLA epitopes for the identified donor inhibitory KIR. KIR-HLA matched group is further classified as Cl, Bw4, Cl-Bw4 and Cl-C2-Bw4 subgroup according to the presence of specific recipient HLA-ligand Cl, Bw4, Cl-Bw4 and Cl-C2-Bw4 C2 respectively.The log-rank statistic of Kaplan-Meier method was used to evaluate the univariate effects on overall survival and disease-free survival. Chi-square test was used in comparison of occurrence of aGVHD, 5 -year relapse, treatment related mortality and the incidence of infections.
Results1. Analysis of HLA class I, II polymorphism and haplotypes in Guangdong Han population14 HLA-A, 23 B, 11 Cw and 13 DRB1 alleles were obtained, Among which the following allele had higher frequency distribution: HLA-A* 11 (0.3292), A*02 (0.2929), A*24 (0.1340), A*33 (0.1268), HLA-B*60 (0.1268), B*75 (0.1197), B*58 (0.1161), B*46 (0.1197), HLA-Cw*03 (0.2580), Cw*07 (0.2016), Cw *01 (0.1708) Cw*08 (0.1056), HLA-DRB1*12 (0.1708), DRB1*14 (0.1197), DRB1*O9 (0.1197) .A total of 9 HLA-A-B, 20 Cw-B, 7 A-Cw, and 8 A-DRB1, 9 B-DRB1, 10 Cw-DRBl haplotypes were found. List as bellow were the haplotypes with very strong linkage disequilibrium (LD): A*02-B*46, A*33-B*58, B*13-Cw*03, B*46-Cw*01, B*51-Cw*14, B*58-Cw*03, B*75-Cw*08, A*02-Cw*01, A*33-Cw*03,A*33-DRBl*17, B*58-DRB1*17, Cw*03-DRBl*17, CwO8-DRBl*122. The gene frequency of HLA-Cw in Guangdong Han population and its significance analysis2.1 The allele frequencies of HLA-Cw*03, 07, 01, 08, 14, 04, 15, 12, 06, 05, 16 were 0.2580, 0.1887,0.1732, 0.1071, 0.0654, 0.0587, 0.0453, 0.0387, 0.0322,0.0127, 0.0032 respectively. It was tested that HLA-Cw in Guangdong Han population was shown to be in Hardy-Weinberg equilibrium (x2=60.35, u=54, P>0.1).2.2 The Cw*06 allele frequency in Guangdong Han population was only 0.0322, much lower than that in Shanghai Han population (P<0.001). The Japanese Cw* 12, 14 gene frequencies were higher than that in Guangdong Han population (P<0.00l). The Cw*01, 03, 08, 14 allele distribution were higher ,while the Cw* *16 frequency was lower in Guangdong Han population than that in European and African. The allele frequencies of Cw*05, 06, 07 in European and Cw*02, 04, 17 in African are higher than that in Guangdong Hanpopulation respectively(P<0.001).2.3 There was a significant difference in allele frequencies between HLA-C1 group (0.8310) and HLA-Cw2 group (0.1399) in Guangdong Han population
3. The relationship between genetic background of donor KIR-recipient HLA and the outcomes in HLA-identical sibling hematopoietic stem cell transplantationIncidence of grade II -IV aGVHD was lower in patients with KIR-HLA match than that in patients with KIR-HLA mismatch. Incidence of grade II -IV aGVHD and fungus infection were lower in Bw4 matched group than that in Bw4 mismatched group. Incidence of grade II -IV aGVHD was lower in patients of Cl-Bw4 subgroup than that in CK Bw4> Cl-C2-Bw4 subgroups. Over all survival in patients of Cl-C2-Bw4 subgroup was higher than that in Cl, Bw4 or Cl-Bw4 subgroups. Fungus infection ratio was higher in patients of Cl subgroup than that in other subgroups. In myeloid disease, patients with Bw4 match had lower incidence of grade II - IV aGVHD and fungus infection when compared with Bw4 mismatched patients, and patients with C2 match had higher overall survival and disease free survival simultaneously when comparing with C2 mismatched patients.Conclusionsl.HLA class I and II alleles in Guangdong Han population have richer polymorphisms. The haplotype distribution possesses territory characteristic.2.It is easier to select a suitable donor in Guangdong Han population for some patients carrying HLA hyplorypes with strong linkage disequilibrium such as A*02-B*46> B*46-Cw*0K A*02-Cw*01> A*33-DRB1*17, B*58- DRBl*^ Cw*03-DRBl*17 and so on .3. HLA-Cw allele in Guangdong Han population is observed through Hardy-Weinberg equilibrium test being in genetic equilibrium. It has richer polymorphisms and character.4.HLA-C1 gene is predominant compared with HLA-C2 gene in Guangdong Han population.5.Donor KIR-recipient HLA genetic background is related with the outcome in HLA-identical sibling HSCT. Donor selection referring to Bw4 or C2 match may
decrease the incidence of aGVHD or improving the OS and DFS accordingly in patients. Selecting Bw4 matched donor may decrease the incidence of fungus infection, but selecting only Cl matched donor may increase the incidence of fungus infection.
引文
1.Couriel D, Caldera H, Charnplin R, et al. Acute graft-versus-host disease:pathophysiology, clinical manifestations, and management. Cancer. 2004,101:1936-46
2.Petersdorf EW, Anasetti C, Martin P J, et al. Tissue typing in support of unrelated hematopoietic cell transplantation. Tissue antigen, 2003,61:1-11
3.Gale RP, Horowitz MM, Ash RC, et al. Identical twin bone marrow transplants for leukemia. Ann Intern Med. 1994,120: 646-52.
4.Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-vs-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989,73:1720-28.
5.Horowitz MM, Gale RP, Sondel PM, et al. Graft-vs-leukemia reactions after bone marrow transplantation. Blood. 1990,75:555-62.
6.Boyington JC, Motyka SA, Schuck P, et al. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature, 2000,405:537-43
7.Brooks AG, Boyington JC, Sun PD: Natural killer cell recognition of HLA class I molecules. Rev Immunogenetics. 2000, 2:433-8
8.Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol. 2002,20:217-51.
9.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 differ in their transmembrane and intracytoplasmic portions. J Exp Med, 1996,183:645-50
10.Uhrberg M, Valiante NM, Shum BP, et al. Human diversity in killer cell inhibitory receptor genes. Immunity, 1997,7:753-63
11.Moretta A, Tambussi G, Bottino C, et al. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J Exp Med, 1995,182:875-84
12.Litwin V, Gumperz J, Parham P, et al. NKBI: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J Exp Med.1994,180:537-43.
13.Uhrberg M. The KIR gene family: life in the fast lane of evolution. Eur J Immunol,2005,35:10-5.
14.Ljunggren HG, Karre K.In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today.1990,11:237-44.
15.Wilson M J, Torkar M, Haude A ,et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA, 2000,97:4778-83.
16.Shilling HG, Guethlein LA, Cheng NW, et al. Allelic polymorphism synergizes with variable gene content to individualize human KIR genotype. J Immunol, 2002,168:2307-15.
17.Hsu KC, Liu XR, Selvakumar A, et al. Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol, 2002, 169:5118-29.
18.Toneva M, Lepage V, Lafay G, et al. Genomic diversity of natural killer call receptor genes in three populations. Tissue Antigen,2001,57:358-62
19.Gardiner CM, Guethlein LA, Shilling HG, et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol. 2001,166:2992-3001
20.Hsu KC, Liu X, Selvakumar A, et al. Killer Iglike receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol, 2002, 169:5123-34
21.Dupont B, Hsu KC. Inhibitory killer Ig-like receptor genes and human leukocyte antigen class I ligands in haematopoietic stem cell transplantation. Curr Opin Immunol. 2004,16:1-10.
22.Shilling HG, Young N, Guethlein LA, et al. Genetic control of human NK cell repertoire. J Immunol. 2002, 169:239-47.
23.Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science.2002,295:2097-2100
24.Koenecke C, Shaffer J, Alexander SI, et al. NK cell recovery, chimerism, function, and recognition in recipients of haploidentical hematopoietic cell transplantation following nonmyeloablative conditioning using a humanized anti-CD2 mAb, Medi-507.Exp Hematol. 2003,31:911-23.
25.Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol. 2004,172:644-65
26.Bishara A, Santis DDe, 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, 63:204-11
27.Cook MA, Milligan DW, 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, 2004,103:1521-6.
28.Hsu KC, Keever-Talor CA, Wilton A, et al. Improved outcome in HLA-identical sibling hematopoietic stem cell transplantation for acute myelogenous leukemia (AML) predicted by KIR and HLA genotypes. Blood. 2005 Feb 24; [Epub ahead of print]
29.Nakajima H, Akastuka Y. The Fifth Nagoya International Blood And Marrow Transplantation Symposium:unlimited possibilities of hematopoietic cell transplantation: lessons from the past and prospects for the future. Int J Hematol. 2004,79:200-4.
30.Torio MA, Muro MO, Ontonon JA,et al.Discrpancies in HLA-C typing in transplantation: comparison of PCR-SSP and serology result. Tram Proc 2002,34:419-20
31.Keresztury L, Rajczy K, Tauszik T, et al. DNA typing revealing high HLA-Cw polymorphism completes availability of major histocompatibility complex loci in forensic medicine.Am J Forensic Med Pathol.2003,24:70-532.Mytilineos J, Christ U, Lempert M, et al. Comparison of typing results by serology and polymerase chain reaction with sequence-specific primers for HLA-Cw in 650individuals.Tissue Antigens.1997,50:395-400.
33.Marsh SGE, Albert ED,Bontrop WF, et al. Nomenclature for Factors of HLA System. Tissue Antigens, 2002,60:407-64
34.肖露露,郝桂琴,叶欣等,HLA基因分型三种操作系统的效果比较。中华微生物和免疫学杂志,2003,23:79—80
35.谭建明,周永昌,唐孝达。组织配型技术与临床应用。人民卫生出版社,2002,91-3。
36.Xiao LL; Hao GQ; Ye X, et al. HLA genotyping by automatic semi-quantitative polymerase chain reaction-reverse sequence specific oligonucleotide. J First Mil med Univ. 2003, 23:58-61
37.Hurley CK, Maiers M, Neg J, et al. Large scale DNA-based typing of HLA-A and HLA-B at low resolution is highly accurate specific and reliable. Tissue Antigen, 2000,55∶352-8
38.陈仁彪,叶根耀,庚镇城等,我国大陆主要少数民族HLA多态性聚类分析和频率分布对中华民族起源的启示。遗传学报,1993,20:389-98
39.Bugawan TL, Klitz W, Blair A, Erlich HA. High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci. Tissue Antigens. 2000,56:392-404.
40.Ando H, Mizuki N,Ando R, et al. High resolution HLA-C typing byPCR-SSP:identification of allelic frequencies and linkage disequilibria frequencies in 604 unrelated random UK Caucasoids and a comparison with serology. Tissue Antigen, 1997, 50:100-11
41.Park M.H, Hwang Y.S, Park K.S, et al. HLA haplotypes in Koreans based on 107 families. Tissue Antigens, 1998,51:347-55
42.Davies SM, Ruggieri L, et al. Evaluation of KIR ligand incompatibility in mismatch unrelated donor hematopoietic transplants Killer immunoglobulin-like receptor. Blood, 2002, 100:3825-7
43.Draghi M, Yawata N, 1 Gleimer M, et al .Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I.Blood,2005,105:2028-35
44.Valiante NM, Lienert K, Shilling HG, et al. Killer cell receptors: keeping pace with MHCclass I evolution. Immunol Rev. 1997;155:155-64.
45.Trowsdale J. Genetic and functional relationships between MHC and NK receptor genes. Immtmity.2001; 15:363-74.
46.Saito S, Ota S, Yamada E, et al. Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens. 2000,56:522-9.
47.Wang H, Tokunaga K, Ishikawa H, et al. A high-resolution genotyping method for HLA-C alleles and possible shared HLA-C-B haplotypes between Japanese and Caucasians. Tissue Antigens, 1997,50:620-6
48.Mar Vales-Gomez ,Huge Reybum, et al. Molecular analyses of the interactions between human NK receptors and their HLA ligands. Human Immunology 2000,61:28-38
49.冯明亮,张雁征等,PCR-SSP分型检测上海汉族人群HLA-Cw位点血清学和非血清学鉴定的等位基因。遗传学报,1998,25:95—102
50.Bugawan TL, Klitz W, Blair A, et al. High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci. Tissue Antigens. 2000,56:392-404.
51.Sanchez-Mazas A, Steiner QG, Grtmdschober C, et al. The molecular determination of HLA-Cw alleles in the Mandenka (West Africa) reveals a close genetic relationship between Africans and Europeans.Tissue Antigens. 2000,56: 303-12.
52.Witt CS, Whiteway JM, et al. Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia.Eur J Immunol, 2002,32:18-29
53.Anastassiou G, Rebmann V, Wagner S, Expression of classic and nonclassic HLA class I antigens in uveal melanoma. Invest Ophthalmol Vis Sci. 2003,44:2016-9.
54.Wang SS, Hildesheim A, Gao X, et al. Comprehensive analysis of human leukocyte antigen class I alleles and cervicalneoplasia in 3 epidemiologic studies. J Infect Dis. 2002 Sep 1;186(5):598-605.
55.Gagne K, Brizard G, Gueglio B, et al, Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum Immunol, 2002, 63:271-80
56.Oberg L, Johansson S, Michaelsson J, et al .Loss or mismatch of MHC class I is sufficient to trigger NK cell-mediated rejection of resting lymphocytes in vivorole of KARAP/DAP12-dependent and-independent pathways. Eur J Immunol 2004,34∶1646-53.
57.Shlomchik WD, Couzens MS, Tang CB, et al, Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999, 285:412-415.
58.Giebel S, Locatelli F, Lamparelli T, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003,102:814-19
59.Morishima Y, Yabe T, Inoko H, et al. 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.
60.Beelen DW, Ottinger H, Ferencik S, et al. Genotypic inhibitory killer immunoglobulin-like receptor Iigand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 2004. DOI 10.1182/blood- 2004-04-1441.
61.Elmaagacli AH, Ottinger H, Koldehoff M, et al. Reduced risk of molecular and haematological relapse in patients with CML after KIR-mismatched haematopoietic stem cell transplantation. Bone Marrow Transplant,2004, 33:S59.
62.Lowe E J, Turner V, Handgretinger R, et al. T-cell allore activity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol, 2003, 123:323-326.
63.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.
64.Shilling HG, McQueen KL, Cheng NW, et al. Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood ,2003,101:3730-40.
65.Schaffer M, Malmberg KJ, Ringden O, et al. Increased infection-related mortalityin in KIR-mismatched unrelated allogeneic hematopoietic stem-cell transplantation. Transplant, 2004, 78:1081-1083.
66.肖露露,马红京,尹晓林等,HLA.Cw在广东汉族人群中的分布频率及其意义的初步分析。中国免疫学杂志,2004,20:256-58
2.Petersdorf EW, Anasetti C, Martin P J, et al. Tissue typing in support of unrelated hematopoietic cell transplantation. Tissue antigen, 2003,61:1-11
3.Gale RP, Horowitz MM, Ash RC, et al. Identical twin bone marrow transplants for leukemia. Ann Intern Med. 1994,120: 646-52.
4.Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-vs-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989,73:1720-28.
5.Horowitz MM, Gale RP, Sondel PM, et al. Graft-vs-leukemia reactions after bone marrow transplantation. Blood. 1990,75:555-62.
6.Boyington JC, Motyka SA, Schuck P, et al. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature, 2000,405:537-43
7.Brooks AG, Boyington JC, Sun PD: Natural killer cell recognition of HLA class I molecules. Rev Immunogenetics. 2000, 2:433-8
8.Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol. 2002,20:217-51.
9.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 differ in their transmembrane and intracytoplasmic portions. J Exp Med, 1996,183:645-50
10.Uhrberg M, Valiante NM, Shum BP, et al. Human diversity in killer cell inhibitory receptor genes. Immunity, 1997,7:753-63
11.Moretta A, Tambussi G, Bottino C, et al. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J Exp Med, 1995,182:875-84
12.Litwin V, Gumperz J, Parham P, et al. NKBI: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J Exp Med.1994,180:537-43.
13.Uhrberg M. The KIR gene family: life in the fast lane of evolution. Eur J Immunol,2005,35:10-5.
14.Ljunggren HG, Karre K.In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today.1990,11:237-44.
15.Wilson M J, Torkar M, Haude A ,et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA, 2000,97:4778-83.
16.Shilling HG, Guethlein LA, Cheng NW, et al. Allelic polymorphism synergizes with variable gene content to individualize human KIR genotype. J Immunol, 2002,168:2307-15.
17.Hsu KC, Liu XR, Selvakumar A, et al. Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol, 2002, 169:5118-29.
18.Toneva M, Lepage V, Lafay G, et al. Genomic diversity of natural killer call receptor genes in three populations. Tissue Antigen,2001,57:358-62
19.Gardiner CM, Guethlein LA, Shilling HG, et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol. 2001,166:2992-3001
20.Hsu KC, Liu X, Selvakumar A, et al. Killer Iglike receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol, 2002, 169:5123-34
21.Dupont B, Hsu KC. Inhibitory killer Ig-like receptor genes and human leukocyte antigen class I ligands in haematopoietic stem cell transplantation. Curr Opin Immunol. 2004,16:1-10.
22.Shilling HG, Young N, Guethlein LA, et al. Genetic control of human NK cell repertoire. J Immunol. 2002, 169:239-47.
23.Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science.2002,295:2097-2100
24.Koenecke C, Shaffer J, Alexander SI, et al. NK cell recovery, chimerism, function, and recognition in recipients of haploidentical hematopoietic cell transplantation following nonmyeloablative conditioning using a humanized anti-CD2 mAb, Medi-507.Exp Hematol. 2003,31:911-23.
25.Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol. 2004,172:644-65
26.Bishara A, Santis DDe, 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, 63:204-11
27.Cook MA, Milligan DW, 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, 2004,103:1521-6.
28.Hsu KC, Keever-Talor CA, Wilton A, et al. Improved outcome in HLA-identical sibling hematopoietic stem cell transplantation for acute myelogenous leukemia (AML) predicted by KIR and HLA genotypes. Blood. 2005 Feb 24; [Epub ahead of print]
29.Nakajima H, Akastuka Y. The Fifth Nagoya International Blood And Marrow Transplantation Symposium:unlimited possibilities of hematopoietic cell transplantation: lessons from the past and prospects for the future. Int J Hematol. 2004,79:200-4.
30.Torio MA, Muro MO, Ontonon JA,et al.Discrpancies in HLA-C typing in transplantation: comparison of PCR-SSP and serology result. Tram Proc 2002,34:419-20
31.Keresztury L, Rajczy K, Tauszik T, et al. DNA typing revealing high HLA-Cw polymorphism completes availability of major histocompatibility complex loci in forensic medicine.Am J Forensic Med Pathol.2003,24:70-532.Mytilineos J, Christ U, Lempert M, et al. Comparison of typing results by serology and polymerase chain reaction with sequence-specific primers for HLA-Cw in 650individuals.Tissue Antigens.1997,50:395-400.
33.Marsh SGE, Albert ED,Bontrop WF, et al. Nomenclature for Factors of HLA System. Tissue Antigens, 2002,60:407-64
34.肖露露,郝桂琴,叶欣等,HLA基因分型三种操作系统的效果比较。中华微生物和免疫学杂志,2003,23:79—80
35.谭建明,周永昌,唐孝达。组织配型技术与临床应用。人民卫生出版社,2002,91-3。
36.Xiao LL; Hao GQ; Ye X, et al. HLA genotyping by automatic semi-quantitative polymerase chain reaction-reverse sequence specific oligonucleotide. J First Mil med Univ. 2003, 23:58-61
37.Hurley CK, Maiers M, Neg J, et al. Large scale DNA-based typing of HLA-A and HLA-B at low resolution is highly accurate specific and reliable. Tissue Antigen, 2000,55∶352-8
38.陈仁彪,叶根耀,庚镇城等,我国大陆主要少数民族HLA多态性聚类分析和频率分布对中华民族起源的启示。遗传学报,1993,20:389-98
39.Bugawan TL, Klitz W, Blair A, Erlich HA. High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci. Tissue Antigens. 2000,56:392-404.
40.Ando H, Mizuki N,Ando R, et al. High resolution HLA-C typing byPCR-SSP:identification of allelic frequencies and linkage disequilibria frequencies in 604 unrelated random UK Caucasoids and a comparison with serology. Tissue Antigen, 1997, 50:100-11
41.Park M.H, Hwang Y.S, Park K.S, et al. HLA haplotypes in Koreans based on 107 families. Tissue Antigens, 1998,51:347-55
42.Davies SM, Ruggieri L, et al. Evaluation of KIR ligand incompatibility in mismatch unrelated donor hematopoietic transplants Killer immunoglobulin-like receptor. Blood, 2002, 100:3825-7
43.Draghi M, Yawata N, 1 Gleimer M, et al .Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I.Blood,2005,105:2028-35
44.Valiante NM, Lienert K, Shilling HG, et al. Killer cell receptors: keeping pace with MHCclass I evolution. Immunol Rev. 1997;155:155-64.
45.Trowsdale J. Genetic and functional relationships between MHC and NK receptor genes. Immtmity.2001; 15:363-74.
46.Saito S, Ota S, Yamada E, et al. Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens. 2000,56:522-9.
47.Wang H, Tokunaga K, Ishikawa H, et al. A high-resolution genotyping method for HLA-C alleles and possible shared HLA-C-B haplotypes between Japanese and Caucasians. Tissue Antigens, 1997,50:620-6
48.Mar Vales-Gomez ,Huge Reybum, et al. Molecular analyses of the interactions between human NK receptors and their HLA ligands. Human Immunology 2000,61:28-38
49.冯明亮,张雁征等,PCR-SSP分型检测上海汉族人群HLA-Cw位点血清学和非血清学鉴定的等位基因。遗传学报,1998,25:95—102
50.Bugawan TL, Klitz W, Blair A, et al. High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci. Tissue Antigens. 2000,56:392-404.
51.Sanchez-Mazas A, Steiner QG, Grtmdschober C, et al. The molecular determination of HLA-Cw alleles in the Mandenka (West Africa) reveals a close genetic relationship between Africans and Europeans.Tissue Antigens. 2000,56: 303-12.
52.Witt CS, Whiteway JM, et al. Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia.Eur J Immunol, 2002,32:18-29
53.Anastassiou G, Rebmann V, Wagner S, Expression of classic and nonclassic HLA class I antigens in uveal melanoma. Invest Ophthalmol Vis Sci. 2003,44:2016-9.
54.Wang SS, Hildesheim A, Gao X, et al. Comprehensive analysis of human leukocyte antigen class I alleles and cervicalneoplasia in 3 epidemiologic studies. J Infect Dis. 2002 Sep 1;186(5):598-605.
55.Gagne K, Brizard G, Gueglio B, et al, Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum Immunol, 2002, 63:271-80
56.Oberg L, Johansson S, Michaelsson J, et al .Loss or mismatch of MHC class I is sufficient to trigger NK cell-mediated rejection of resting lymphocytes in vivorole of KARAP/DAP12-dependent and-independent pathways. Eur J Immunol 2004,34∶1646-53.
57.Shlomchik WD, Couzens MS, Tang CB, et al, Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999, 285:412-415.
58.Giebel S, Locatelli F, Lamparelli T, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003,102:814-19
59.Morishima Y, Yabe T, Inoko H, et al. 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.
60.Beelen DW, Ottinger H, Ferencik S, et al. Genotypic inhibitory killer immunoglobulin-like receptor Iigand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 2004. DOI 10.1182/blood- 2004-04-1441.
61.Elmaagacli AH, Ottinger H, Koldehoff M, et al. Reduced risk of molecular and haematological relapse in patients with CML after KIR-mismatched haematopoietic stem cell transplantation. Bone Marrow Transplant,2004, 33:S59.
62.Lowe E J, Turner V, Handgretinger R, et al. T-cell allore activity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol, 2003, 123:323-326.
63.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.
64.Shilling HG, McQueen KL, Cheng NW, et al. Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood ,2003,101:3730-40.
65.Schaffer M, Malmberg KJ, Ringden O, et al. Increased infection-related mortalityin in KIR-mismatched unrelated allogeneic hematopoietic stem-cell transplantation. Transplant, 2004, 78:1081-1083.
66.肖露露,马红京,尹晓林等,HLA.Cw在广东汉族人群中的分布频率及其意义的初步分析。中国免疫学杂志,2004,20:256-58