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

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) has a critical role in the downregulation of the immune response. 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, exon 1 +49A/G and within the 3'untranslated region CT60G/A. Each one of these SNPs may influence the cell surface expression of the CTLA-4 molecule, the former affecting CTLA-4 gene expression, the +49A/G resulting in an amino acid substitution Thr17Ala in the leader peptide and CT60 determining the efficiency of the splicing and production of sCTLA-4. Sixtythree 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. The association of each genotype with ARE was evaluated. Allele frequencies in both groups of patients (ARE and non-ARE) were similar at two positions, -1147T/C (ARE T af = 19.2%, C af = 80.8%; non-ARE T af = 22.2%, C af = 75.9%) and +49A/G (ARE A af = 65.0%, G af = 35.0%; non-ARE A af = 65.4%, G af = 34.6%). Regarding +49 genotype frequencies, we noted a different distribution between the two groups (G/G: ARE af = 16.7%, non-ARE af = 3.8%, p = ns; A/G: ARE af = 36.9%, non-ARE af = 61.5%; A/A: ARE af = 46.7%, non-ARE af = 34.6%) and, in particular, an increased frequency in ARE of G/G genotypes, associated with a decreased expression of CTLA-4 molecule. Regarding CT60 dimorphism, noteworthy was the identification of a significant higher incidence of CT60 A/A genotype, previously considered protective, in ARE compared to non-ARE group (p = 0.024, ?2 = 2.988, pc = 0.048 28.6% to 3.6%, respectively). 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 what was 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.