title: Influence of cytotoxic T-lymphocyte antigen-4 polymorphisms on acute rejection onset of cadaveric renal transplants.
abstract: We retrospectively examined in cadaveric renal transplants the association between acute rejection episodes (ARE) and single nucleotide polymorphisms (SNPs) localized in the cytotoxic T-lymphocyte antigen (CTLA)-4 promoter, -1147T/C and -318C/T, in exon 1 +49A/G and within the 3' untranslated region (UTR) CT60G/A. Each one of these SNPs may influence the cell surface expression of the CTLA-4 molecule. Seventy-two cadaveric renal transplant recipients with at least 6 month's follow-up were genotyped for CTLA-4 dimorphisms using direct sequencing of specific polymerase chain reaction products. Allele frequencies in both groups of patients with or without acute rejection (ARE and non-ARE) did not show significant differences in various nucleotide positions. At the level of genotype frequency we first noted a positive association to acute rejection of G/G genotypes (ARE af = 14.7%, non-ARE af = 5.9%) for the +49 (cod. 17), which was associated with decreased expression of the CTLA-4 full-length molecule. In contrast, the AG genotype seemed to be protective (61.8% vs 32.4%, P = .028; odds ratio [OR] = 0.2961). Regarding the CT60G/A dimorphism, noteworthy was the identification of a significantly higher incidence of CT60 A/A genotype in ARE compared with non-ARE group (29.7% vs 8.6%; Yates P = .035; OR = 4.51). Such association of protective AA genotype with ARE, as observed also in autoimmunity, was associated with an increased level of sCTLA-4 induced by the polymorphism, which blocks B7-flCTLA-4 interactions, enhancing T-cell reactivity by preventing transduction of inhibitory signals. Considering the various polymorphic sites in the haplotype, we observed a significant increase in ARE among patients of the CTLA4 +49A/CT60A (HF = 51.5% vs 29.5%; P = .014; OR = 2.545) and a reduction among the +49A/CT60G (17.6% vs 33.8%; P = .04; OR = 0.4193) 2-loci haplotype, As regards the -1147/-318/+49/CT60 CTLA-4 4-loci haplotypes, we observed a significantly higher frequency of the CCAA haplotype in ARE patients comparison with those free of rejection (HF = 51.8% vs 31.1%, P = .046 OR = 2.363). These findings are consistent with those observed in allogeneic stem cell transplantation, wherein patients with CT60 AA showed a major incidence of graft-versus-host disease. An association of protective AA genotype with ARE, as observed also in autoimmunity was associated with an increased level of sCTLA-4 induced by this polymorphism, which blocking the B7-flCTLA-4 interaction, would enhance T-cell reactivity by preventing transduction of inhibitory signals.
authors.affiliation: CNR Institute of Translational Pharmacology, L'Aquila, Italy. Electronic address: angelica.canossi@cnr.it.
authors.forename: A
authors.initials: A
authors.lastname: Canossi
authors.forename: A
authors.initials: A
authors.lastname: Aureli
authors.forename: F
authors.initials: F
authors.lastname: Delreno
authors.forename: S
authors.initials: S
authors.lastname: Iesari
authors.forename: C
authors.initials: C
authors.lastname: Cervelli
authors.forename: K
authors.initials: K
authors.lastname: Clemente
authors.forename: A
authors.initials: A
authors.lastname: Famulari
authors.forename: F
authors.initials: F
authors.lastname: Pisani
authors.forename: F
authors.initials: F
authors.lastname: Papola
mesh_terms: D060908:CTLA-4 Antigen / Q000235:genetics*; D002102:Cadaver; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation; D011110:Polymorphism, Genetic
chemical_list: D060908:CTLA-4 Antigen