CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors

• Published in: Blood 2007-07, Vol.110 (1), p.461-467
• Main Authors: Pérez-García, Arianne, De la Cámara, Rafael, Román-Gómez, Jose, Jiménez-Velasco, Antonio, Encuentra, Maite, Nieto, Jose B., de la Rubia, Javier, Urbano-Ispizúa, Alvaro, Brunet, Salut, Iriondo, Arturo, González, Marcos, Serrano, David, Espigado, Ildefonso, Solano, Carlos, Ribera, Josep M., Pujal, Josep M., Hoyos, Montserrat, Gallardo, David
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antigens, CD - genetics; Antigens, Differentiation - genetics; Biological and medical sciences; Child; Child, Preschool; CTLA-4 Antigen; Female; Genotype; Graft vs Host Disease - etiology; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cell Transplantation - mortality; Histocompatibility - genetics; HLA Antigens - immunology; Humans; Infant; Male; Medical sciences; Middle Aged; Polymorphism, Genetic; Siblings; Survival Rate; Transplantation, Homologous; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-01-069781

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 genotyped 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 [CI], 1.75-8.22), due to a higher risk of relapse (P = .049; HR, 1.71; 95% CI, 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% CI, 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.