CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors
CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors
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DOI：
10.1182/blood-2007-01-069781
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发表时间：
2007-07-01
期刊：
影响因子：
20.3
通讯作者：
Gallardo, David
中科院分区：
文献类型：
--
作者：
Pérez-García, Arianne;De la Cámara, Rafael;Gallardo, David
CTLA-4是下调T细胞活化的抑制性分子。虽然CTLA-4的多态性与自身免疫性疾病相关，但其与异基因造血干细胞移植（allo-HSCT）后临床结果的相关性尚未被探索。共5 CTLA-4单核苷酸多态性基因分型的536 HLA相合同胞供体的异基因造血干细胞移植。基因型与患者移植后结果的相关性进行了测试。在60名健康对照者中测定了这些多态性对细胞毒性T淋巴细胞抗原4（CTLA-4）mRNA和蛋白质产生的影响。我们观察到在CT60和+49处存在G等位基因的情况下，可溶性CTLA-4同种型的mRNA表达减少。接受来自CT60位至少有1个G等位基因供体的干细胞的患者总体生存率更差（5年时56.2% vs 69.8%; P = 0.001;风险比[HR]，3.80; 95%置信区间[Cl]，1.75-8.22），由于复发风险较高（P = 0.049; HR，1.71; 95% CI，1.00-2.93）。急性移植物抗宿主病（aGVHD）在接受CT60 AA干细胞的患者中更常见（P = 0.033; HR，1.54; 95% CI，1.03-2.29）。这是第一项报告CTLA-4多态性与allo-HSCT后临床结局相关的研究。CT60基因型影响复发和aGVHD，可能是由于其对CTLA-4选择性剪接的作用。
CTLA-4 is an inhibitory molecule that down-regulates T-cell activation. Although polymorphisms at CTLA-4 have been correlated with autoimmune diseases their association with clinical outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has yet to be explored. A total of 5 CTLA-4 single-nucleotide polymorphisms were geno-typed on 536 HLA-identical sibling donors of allo-HSC transplants. Genotypes were tested for an association with patients' posttransplantation outcomes. The effect of the polymorphisms on cytotoxic T-lymphocyte antigen 4 (CTLA-4) mRNA and protein production were determined in 60 healthy control participants. We observed a reduction in the mRNA expression of the soluble CTLA-4 isoform in the presence of a G allele at CT60 and +49. Patients receiving stem cells from a donor with at least 1 G allele in position CT60 had worse overall survival (56.2% vs 69.8% at 5 years; P = .001; hazard ratio [HR], 3.80; 95% confidence interval [Cl], 1.75-8.22), due to a higher risk of relapse (P = .049; HR, 1.71; 95% Cl, 1.00-2.93). Acute graft-versus-host disease (aGVHD) was more frequent in patients receiving CT60 AA stem cells (P = .033; HR, 1.54; 95% Cl, 1.03-2.29). This is the first study to report an association between polymorphisms at CTLA-4 and clinical outcome after allo-HSCT. The CT60 genotype influences relapse and aGVHD, probably due to its action on CTLA-4 alternative splicing.