Background: Previous studies have demonstrated that CD4+Foxp3+ regulatory T (Treg) cells regulate HBV-related disease progression. The present study investigated the association between Treg cells and the outcomes in HBV-related liver transplant (LT) patients. Methods: This study comprised 93 living related donor LT recipients, including 24 patients infected with HBV. By using the genomic DNA isolated from the peripheral blood of the patients, a single nucleotide polymorphism (SNP), rs3761548, in Foxp3 gene, which encodes a transcription factor essential for the development and function of Treg cells, was determined by using PCR-RFLP. To monitor alloimmune responses, multiparameter MLR assay using CFSE was performed prior to LT and at regular intervals after LT. The basic immunosuppressive regimen comprised tacrolimus and methylprednisolone, with gradual tapering of doses. The optimal dosages of the immunosuppressants were determined by the immune monitoring. Results: The frequency of the AA/AC genotype at rs3761548, which causes defective transcription of the Foxp3 gene, was higher in LT patients with HBV-related fulminant hepatitis (60%, n=5) than in LT patients with HBV-related liver cirrhosis (HBVc) (26%, n=19). The frequency of the CC genotype, which leads to competent transcription of the Foxp3 gene, was higher in LT patients with HBVc (74%, n=19) than in HBV-unrelated LT patients with liver cirrhosis (60%, n=74). These findings suggest that HBV-related LT patients are immunological hypo-responders. Similarly, LT patients with HBVc showed lower T-cell responses against allostimulation in MLR assay even prior to LT than those shown by patients with other original diseases, including HCV infection. None of the LT patients with HBVc developed acute cellular rejection (ACR) (0/19), whereas 11% (4/35) of patients with HCV developed MLR-proven ACR. Notably, all of the patients who suffered from ACR had the AA or AC genotype. In the 19 patients with HBVc, immunosuppressants were completely discontinued in 3 patients. The proportion of Treg cells in peripheral blood of those tolerant patients was significantly higher than that in non-tolerant patients. In contrast, in none of the 35 patients with HCV, immunosuppressants were discontinued. Conclusions: The Foxp3 gene SNP is significantly correlated to the clinical outcomes in LT patients. LT patients with HBVc are immunological hypo-responders in response to allostimulation.

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