CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors.
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.
Pérez-García
Arianne
A
Clinical Hematology Department, Alloreactivity Unit, Laborateri de Recerca Translacional, Institut Català d'Oncologia, Hospital Duran i Reynals, Barcelona, Spain.
De la Cámara
Rafael
R
Román-Gómez
Jose
J
Jiménez-Velasco
Antonio
A
Encuentra
Maite
M
Nieto
Jose B
JB
de la Rubia
Javier
J
Urbano-Ispizúa
Alvaro
A
Brunet
Salut
S
Iriondo
Arturo
A
González
Marcos
M
Serrano
David
D
Espigado
Ildefonso
I
Solano
Carlos
C
Ribera
Josep M
JM
Pujal
Josep M
JM
Hoyos
Montserrat
M
Gallardo
David
D
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000209:etiology; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006648:Histocompatibility / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D035781:Siblings; D015996:Survival Rate; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006680:HLA Antigens