| BackgroundLiver transplantation (LT) is generally considered as the most effective treatment for HBV-related liver diseases. However, HBV-reinfection after LT is a frequent clinical problem. Despite the prophylactic use of HBIG and nucleoside analogous lamivudine (LAM), the incidence of HBV recurrence was reported to be 0-10% even in those most distinguished centers. Previous studies have demonstrated that HBV-specific CD4+ T lymphocyte was activated in LT recipients with HBV recurrence, which indicated that T cell-mediated immunity may play an important role in the clearance of HBV even under maintenance of immunosuppressant after transplantation. The activation and differentiation of CD4+ T lymphocyte is provoked by a combinedeffect of antigen peptide-MHC compound binding to T-cell receptor (TCR) and interaction of antigen presenting cell (APC) with T lymphocyte through costimulatory molecules. B7 family, including the functional molecules B7-1 (CD80) and B7-2 (CD86), play a significant role in the modulation of either activating or suppressing of T lymphocyte. Upon engaging their ligand CD28 on T cells, CD80 and CD86 on antigen-presenting cells help to mount an efficient immune response which provides a crucial signal mediating the activation of T cells into effector cells. Meanwhile, CTLA-4 (CD152), a homologue of CD28 and expressed on activated regulatory T cells, acts as a down regulator of immune responses after binding to B-7 molecules.It has been demonstrated that CTLA-4 mediated signal, upon interaction with CD80 or CD86, actively inhibits the production of IL-2 and cell-cycle progression of T cells. The increasing knowledge on the signaling pathway of antigen presenting and T lymphocyte activation has led our concentration on the individual differences of T cell immunity resulted from single-nucleotide polymorphisms (SNPs).In the last few years, several genetic SNPs have been detected in costimulatory molecule CD86 (B7-2) and its ligand CTLA-4 expressed on the T cytomembrane. The SNP at +49 of CTLA-4 gene was found to significantly alter the intensity of T cell-mediated immunity, resulting in the individual difference of a series of autoimmune diseases and the incidence of post transplant allograft rejection. Recentstudies also suggested that the CTLA-4 +49 SNP influenced the recovery from HBV infection as well as altering the vigor of response to the antiviral treatment in patients with chronic hepatitis C. However, this gene locus has not been examined in HBV recurrence after LT.In view of the importance of B7-CTLA-4 signaling pathway in the regulation of T cell immunity against various pathogens, this study was designed to check the relationship of HBV recurrence to this known SNP.Materials and methods167 patients with HBV-related end stage liver diseases who underwent orthotopic liver transplantation from cadaveric donors between 2003 July and 2005 June in our center and treated with a combined therapy of lamivudine and HBIg were enrolled in this retrospective study.Recipient genomic DNA was extracted from explanted liver graft. CTLA-4 gene was amplified by PCR. RFLP array and DNA sequencing were used to determine the SNPs of CTLA-4 gene respectively. The patients were divided into two groups according to the incidence of HBV recurrence. The correlation between HBV recurrence and recipient CTLA-4 genotype as well as a series of risk factors including recipient pretransplant serum HBV DNA concentration and posttransplant serum HBsAb titre were then investigated.Statistical analysis was performed by the statistical software package SPSS 13.0. Cbi-square tests were used for analyzing differences between CTLA-4 polymorphisms and HBV recurrence. Between-two-group differences of HBV DNA concentration and HBsAb titre were calculated by use of Mann-Whitney U test P<0.05 was considered statistically significantResultsAfter LT, patients were followed up for a median time of 25.32 months. The mean age of the 167 recipients was 46±8.3 years (range 26-67), being most of them males (91.6%). The primary liver diseases were HBV related decompansate liver cirrhosis, hepatic cellular carcinoma and fulminant hepatitis B. HBV recurrence occurred in 24 patients, with a mean recurrence time of 8 months (range 1-33 months). The overall incidence of HBV recurrence after LT reached 14.4%.The distribution of CTLA-4 +49A/G genotypes significantly differed between Recurrence and Non-Recurrence groups (P=0.032). The incidence of HBV re-infection in recipients with GG, GA and AA genotype was 6.67% (5/75), 19.7% (15/76) and 25% (4/20), respectively. There was also a statistical significance in the allelic distribution of CTLA-4 +49 between the Recurrence and Non-Recurrence groups (P=0.013, OR 2.176, 95% CI 1.170-4.046). The G allele frequency in the Non-Recurrence group was 70.3%, in contrast to 52.8% in the Recurrence group.Further investigation for the relation of HBV recurrence between other risk factors indicated posttransplant HBsAb level (P =0.004) were independently associated with the development of post-LT HBV recurrence. The pretransplant serum HBV DNA level in the recipient, as a representation of viral load, was not significantly associated with HBV recurrence in this study.Conclusions1. The mechanism of HBV recurrence after OLT in patients with HBV related end stage liver diseases was complex, despite the prophylactic administration of lamivudine and HBIg, there was a major between-person difference on the incidence of HBV recurrence in different individuals.2. CTLA-4 GG genotype was related to a reduced risk on the incidence of HBVrecurrence.3. There may be other potential SNP locations which could influence the out come of LT for HBV related diseases. Further investigations with expanded samples of the same study group should be carried out... |
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