INFLUENCE OF CTLA-4 POLYMORPHISMS ON ACUTE REJECTION ONSET OF CADAVERIC RENAL TRANSPLANTS.

We retrospectively examined in cadaveric renal transplants the association between acute rejection episodes (ARE) and single nucleotide polymorphisms (SNPs) localized in the CTLA-4 promoter, -1147T/C and -318C/T, in exon 1 +49A/G and within the 3' 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 months follow-up were examined and genotyped for CTLA-4 dimorphisms by using direct sequencing of specific PCR products. Allele frequencies in both groups of patients with or without acute rejection (ARE and non-ARE) did not show significant differences in the various nucleotide positions. At the level of genotype frequency we firstly noted for the +49 (cod.17) a positive association to acute rejection of G/G genotypes (ARE af=14.7%, non-ARE af=5.9%), associated with a decreased expression of CTLA-4 full length molecule, on the other hand, the AG genotype seemed to be protective (61.8% vs 32.4%, p=0.028 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 to non-ARE group (29.7% vs. 8.6%, Yates's p=0.032, OR=4.51). Such association of protective AA genotype with ARE could be determined, as observed also in autoimmunity, by an increased level of sCTLA-4 induced by such a polymorphism, which blocking the B7-flCTLA-4 interaction, would enhance T-cell reactivity by preventing the transduction of inhibitory signals.Considering the various polymorphic sites in haplotype, we evidenced a significant increase in ARE patients of the CTLA4 +49A/CT60A (HF=51.5% vs. 29.5%, p=0.014 OR=2.545) and a reduction of the +49A/CT60G (17.6% vs. 33.8%, p=0.04 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 in comparison to those without rejection (HF=51.8% vs 31.1%, p=0.046 OR=2.363).Regarding CT60 dimorphism, noteworthy was the identification of a significant higher incidence of CT60 A/A protective genotype in ARE compared to non-ARE group (p=0.024, X2= 2.988, ARE: af=28.6%, non-ARE: af=3.6%). In addition, a significant increase of the CTLA4 +49A-CT60A haplotype was evidenced in ARE patients (p=0.0011, 38.9% to 14.6%). These findings seem to be in agreement with that observed in allogeneic stem cell transplantation, in which patients with CT60 AA had a major incidence of GvHD. Such association of protective AA genotype with ARE could be determined, as observed also in autoimmunity, by an increased level of sCTLA-4 induced by such a polymorphism, which blocking the B7-flCTLA-4 interaction, would enhance T-cell reactivity by preventing the transduction of inhibitory signals.