IL-10基因-592(C→A)位点单核苷酸多态性与儿童异基因造血干细胞移植后移植物抗宿主病的相关性研究
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摘要
目的:研究IL-10基因-592(C→A)位点(rs1800872)单核苷酸多态性(single nucleotide polymorphism, SNP)供者和受者基因型对儿童异基因造血干细胞移植(allo-HSCT)后移植物抗宿主病(graft versus host disease, GVHD)的影响。方法:对2011年1月至2017年7月在首都医科大学附属北京儿童医院血液肿瘤中心进行异基因造血干细胞移植的97例儿童患者及与之配对的71例供者进行基因型检测。提取外周血基因组DNA,采用TaqMan SNP Genotyping Assays探针法检测该位点SNP基因型,并结合临床资料分析与移植物抗宿主病及移植相关死亡率的相关性。结果:AA基因型恶性疾病患者中Ⅱ-Ⅳ度急性移植物抗宿主病(aGVHD)的发生率(9.1%),较AC+CC基因型恶性疾病患者(43.5%)显著降低(P <0.01),且胃肠道受累的概率也显著降低(9.1%vs 39.1%)(P <0.05)。在全部患者及非恶性疾病患者中,不同基因型患者在Ⅱ-Ⅳ度aGVHD的发生率方面差异无统计学意义。患者基因型对慢性移植物抗宿主病(cGVHD)的发生率以及移植后1年移植相关死亡率(transplantation-related mortality, TRM)影响差异无统计学意义。在非恶性疾病中,供者AA基因型,发生肝脏aGVHD的概率(23.1%)较AC+CC基因型明显增高(0.0%)(P <0.05)。不同供者基因型对患者移植后Ⅱ-Ⅳ度aGVHD的发生率、cGVHD的发生率、移植后1年TRM的分析均无明显差异。结论:在儿童异基因造血干细胞移植中,患者IL-10基因-592(C→A)位点AA基因型是儿童恶性疾病移植后Ⅱ-Ⅳ度aGVHD的发生率降低以及胃肠道受累减少的有利因素;供者AA基因型,是非恶性疾病移植后肝脏aGVHD的不利因素。
Objective: To study the association between IL-10 gene-592(C→A)(rs1800872) single nucleotide polymorphism(SNP) and the graft versus host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT) in children. Methods: Ninety-seven childhood patients and seventy-one donors in the Hematology Oncology Center of Beijing Children's Hospital from Jan 2011 to Jul 2017 were enrolled in this study. The genomic DNA was extracted from peripheral blood cells and the SNP genotype was analyzed using TaqMan SNP genotyping assay. Results:In malignant patients with AA genotype, the incidence of Ⅱ-Ⅳ grade acute GVHD(aGVHD) was lower than that in patients with AC and CC genotype(9.1% vs 43.5%)(P<0.01), and the gastrointestinal aGVHD rate was also lower(9.1% vs 39.1%)(P<0.05). There's no significant association between patients' genotype and Ⅱ-Ⅳ grade aGVHD in total patients and non-malignant patients. Also, the genotype in patients did not corelate with chronic GVHD(cGVHD)and 1 year transplantation-related mortality(TRM). In cases who received HSCT of donors with AA genotype, the liver aGVHD rate was higher than that in cases who received HSCT of donors with AC and CC genotype(23.1% vs 0.0%)(P<0.05), but the genotype in donors did not correlate with Ⅱ-Ⅳ grade aGVHD, cGVHD and 1 year TRM. Conclusion:AA genotype in the IL-10 gene-592(C→A)(rs1800872) single nucleotide polymorphism in patients protects pediatric malignant patients against Ⅱ-Ⅳ grade aGVHD and gastrointestinal aGVHD after allo-HSCT. AA genotype in donors is a risk factor for liver aGVHD after allo-HSCT in non-malignant disease.
Objective: To study the association between IL-10 gene-592(C→A)(rs1800872) single nucleotide polymorphism(SNP) and the graft versus host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT) in children. Methods: Ninety-seven childhood patients and seventy-one donors in the Hematology Oncology Center of Beijing Children's Hospital from Jan 2011 to Jul 2017 were enrolled in this study. The genomic DNA was extracted from peripheral blood cells and the SNP genotype was analyzed using TaqMan SNP genotyping assay. Results:In malignant patients with AA genotype, the incidence of Ⅱ-Ⅳ grade acute GVHD(aGVHD) was lower than that in patients with AC and CC genotype(9.1% vs 43.5%)(P<0.01), and the gastrointestinal aGVHD rate was also lower(9.1% vs 39.1%)(P<0.05). There's no significant association between patients' genotype and Ⅱ-Ⅳ grade aGVHD in total patients and non-malignant patients. Also, the genotype in patients did not corelate with chronic GVHD(cGVHD)and 1 year transplantation-related mortality(TRM). In cases who received HSCT of donors with AA genotype, the liver aGVHD rate was higher than that in cases who received HSCT of donors with AC and CC genotype(23.1% vs 0.0%)(P<0.05), but the genotype in donors did not correlate with Ⅱ-Ⅳ grade aGVHD, cGVHD and 1 year TRM. Conclusion:AA genotype in the IL-10 gene-592(C→A)(rs1800872) single nucleotide polymorphism in patients protects pediatric malignant patients against Ⅱ-Ⅳ grade aGVHD and gastrointestinal aGVHD after allo-HSCT. AA genotype in donors is a risk factor for liver aGVHD after allo-HSCT in non-malignant disease.
引文
1DickinsonAM,CharronD.Non-HLAimmunogeneticsin hematopoietic stem cell transplantation. Curr Opin Immunol, 2005;17(5):517-525.
2 Mullighan C, Heatley S, Doherty K, et al. Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation. Transplantation, 2004; 77(4):587-596.
3 Reddy P, Ferrara JL. Immunobiology of acute graft-versus-host disease. Blood Rev, 2003; 17(4):187-194.
4 Holler E, Roncarolo MG, Hintermeier-Knabe R, et al. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation, Bone Marrow Transplant,2000; 25(3):237-241.
5 Linder H, Holler E, Gerbitz A, et al. Influence of bacterial endotoxin on radiation-induced activation of human endothelial cells in vitro and in vivo:interleukin-10 protects against transendothelial migration. Transplantation, 1997; 64(9):1370-1373.
6 Sternbrink K, Wolfl M, Jonuleit H, et al. Induction of tolerance by IL-10-treated dendritic cells. J Immunol, 1997; 159(10):4772-4780.
7 Willems F, Marchant A, Delville JP, et al. Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunol, 1994; 24(4):1007-1009.
8 Middlenton PG, Taylor PR, Jackson G, et al. Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. Blood, 1998; 92(10):3943-3948.
9 Lin MT, Storer B, Martin PJ, et al. Relation of an interleukin-10promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med, 2003;349(23):2201-2210.
10 ChoIH,SongYK,KimMG,etal.Associationbetween interleukin-10 promoter gene polymorphisms and acute graftversus-host disease after hematopoietic stem cell transplantation:a systematic review and meta-analysis. Hematol, 2015; 20(3):121-128.
11 杨志洛,邱桥成,丁子轩,等. IL10-592位点AA基因型对HLA-10/10全相合无关供者异基因造血干细胞移植预后的影响.中华血液学杂志, 2016; 37(5):372-376.
12 徐宏贵.造血干细胞移植后并发症及处理.实用小儿血液病学,2014; 562-563.
13 Zhu P, Xie L, Yang Y, et al. IL-10 promoter polymorphism associatedwithdecreasedriskofaGvHDafterstemcell transplantation:a meta-analysis. Int J Hematol, 2013; 98(1):102-111.
14 Moore KW, O'Garra A, de Waal Malefyt R, et al. Interleukin-10.Annu Rev Immunol, 1993;11:165-190.
15 Kube D, Platzer C, von Knethen A, et al. Isolation of the human interleukin 10 promoter. Characterization of the promoteractivity in Burkitt's lymphoma cell lines. Cytokine, 1995; 7(1):1-7.
16 Gibson AW, Edberg JC, WU J, et al. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol,2001; 166(6):3915-3922.
17 Tegoshi H, Hasegawa G, Obayashi H, et al. Polymorphisms of interferon-gamma gene CA-repeat and interleukin-10 promoter region(-592A/C)in Japanese type I diabetes. Hum Immunol, 2002;63(2):121-128.
18 Nakasone H, Fukuda T, Kanda J, et al. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. Bone Marrow Transplant, 2015; 50(4):559-565.
19 Ringdén O, Erkers T, Aschan J, et al. A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation. J Intern Med,2013; 274(2):153-162.
2 Mullighan C, Heatley S, Doherty K, et al. Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation. Transplantation, 2004; 77(4):587-596.
3 Reddy P, Ferrara JL. Immunobiology of acute graft-versus-host disease. Blood Rev, 2003; 17(4):187-194.
4 Holler E, Roncarolo MG, Hintermeier-Knabe R, et al. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation, Bone Marrow Transplant,2000; 25(3):237-241.
5 Linder H, Holler E, Gerbitz A, et al. Influence of bacterial endotoxin on radiation-induced activation of human endothelial cells in vitro and in vivo:interleukin-10 protects against transendothelial migration. Transplantation, 1997; 64(9):1370-1373.
6 Sternbrink K, Wolfl M, Jonuleit H, et al. Induction of tolerance by IL-10-treated dendritic cells. J Immunol, 1997; 159(10):4772-4780.
7 Willems F, Marchant A, Delville JP, et al. Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunol, 1994; 24(4):1007-1009.
8 Middlenton PG, Taylor PR, Jackson G, et al. Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical sibling transplants. Blood, 1998; 92(10):3943-3948.
9 Lin MT, Storer B, Martin PJ, et al. Relation of an interleukin-10promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med, 2003;349(23):2201-2210.
10 ChoIH,SongYK,KimMG,etal.Associationbetween interleukin-10 promoter gene polymorphisms and acute graftversus-host disease after hematopoietic stem cell transplantation:a systematic review and meta-analysis. Hematol, 2015; 20(3):121-128.
11 杨志洛,邱桥成,丁子轩,等. IL10-592位点AA基因型对HLA-10/10全相合无关供者异基因造血干细胞移植预后的影响.中华血液学杂志, 2016; 37(5):372-376.
12 徐宏贵.造血干细胞移植后并发症及处理.实用小儿血液病学,2014; 562-563.
13 Zhu P, Xie L, Yang Y, et al. IL-10 promoter polymorphism associatedwithdecreasedriskofaGvHDafterstemcell transplantation:a meta-analysis. Int J Hematol, 2013; 98(1):102-111.
14 Moore KW, O'Garra A, de Waal Malefyt R, et al. Interleukin-10.Annu Rev Immunol, 1993;11:165-190.
15 Kube D, Platzer C, von Knethen A, et al. Isolation of the human interleukin 10 promoter. Characterization of the promoteractivity in Burkitt's lymphoma cell lines. Cytokine, 1995; 7(1):1-7.
16 Gibson AW, Edberg JC, WU J, et al. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol,2001; 166(6):3915-3922.
17 Tegoshi H, Hasegawa G, Obayashi H, et al. Polymorphisms of interferon-gamma gene CA-repeat and interleukin-10 promoter region(-592A/C)in Japanese type I diabetes. Hum Immunol, 2002;63(2):121-128.
18 Nakasone H, Fukuda T, Kanda J, et al. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. Bone Marrow Transplant, 2015; 50(4):559-565.
19 Ringdén O, Erkers T, Aschan J, et al. A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation. J Intern Med,2013; 274(2):153-162.