Verma Sapana, Tanaka Yuka, Shimizu Seiichi, Tanimine Naoki, Ohdan Hideki
Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences Hiroshima University Hiroshima Japan.
Hepatol Commun. 2017 Jun 8;1(5):406-420. doi: 10.1002/hep4.1052. eCollection 2017 Jul.
Previous studies have found that preferential accumulation of regulatory T (Treg) cells in liver allografts during acute cellular rejection (ACR) is associated with less severe rejection, suggesting a role of Treg cells in preventing excessive progress of ACR. We investigated the impact of single nucleotide polymorphisms (SNPs) in the Forkhead box P3 () gene, a master regulator gene of Treg cells, on ACR severity in liver transplant (LT) recipients. In total, 102 living donor LT patients were enrolled in this study and categorized into no rejection (n = 86), steroid-sensitive acute rejection (SSAR; n = 11), and steroid-resistant acute rejection (SRAR; n = 5). SNPs -3499 A/G (rs3761547), -3279 A/C (rs3761548), and -924 A/G (rs2232365) were genotyped using the polymerase chain reaction restriction fragment length polymorphism technique. T-cell responses to allostimulation were evaluated by the mixed lymphocyte reaction assay. We found no statistical association between the SNP genotype frequencies and ACR incidence. However, significantly higher incidence of SRAR was observed in LT patients with the rs3761548 A/C+A/A genotype than in those with the C/C genotype (A/C+A/A versus C/C; no rejection, SSAR, SRAR, 85.71%, 0%, 14.29% versus 83.58%, 16.42%, 0%, respectively; 0.0005). The mixed lymphocyte reaction assay performed at the time of ACR diagnosis showed higher anti-donor CD4 T-cell responses in patients carrying rs3761548 A/C+A/A than in those with the C/C genotype ( 0.019). No significant association was observed between the incidence of SRAR and either rs3761547A/G or rs2232365 A/G. Infectious complications and overall survival were not related to SNPs. : Our findings indicate that SNP rs3761548 A/C might be a predisposing factor for SRAR after liver transplantation. ( 2017;1:406-420).
先前的研究发现，在急性细胞排斥反应（ACR）期间，肝脏同种异体移植中调节性T（Treg）细胞的优先积累与较轻的排斥反应相关，这表明Treg细胞在防止ACR过度进展中发挥作用。我们研究了Treg细胞的主要调节基因叉头框P3（FOXP3）中的单核苷酸多态性（SNP）对肝移植（LT）受者ACR严重程度的影响。本研究共纳入102例活体供肝LT患者，分为无排斥反应组（n = 86）、类固醇敏感急性排斥反应组（SSAR；n = 11）和类固醇抵抗急性排斥反应组（SRAR；n = 5）。采用聚合酶链反应-限制性片段长度多态性技术对SNP -3499 A/G（rs3761547）、-3279 A/C（rs3761548）和-924 A/G（rs2232365）进行基因分型。通过混合淋巴细胞反应试验评估T细胞对同种异体刺激的反应。我们发现SNP基因型频率与ACR发生率之间无统计学关联。然而，rs3761548 A/C+A/A基因型的LT患者中SRAR的发生率显著高于C/C基因型患者（A/C+A/A与C/C；无排斥反应、SSAR、SRAR，分别为85.71%、0%、14.29%与83.58%、16.42%、0%；P = 0.0005）。在ACR诊断时进行的混合淋巴细胞反应试验显示，携带rs3761548 A/C+A/A的患者抗供体CD4 T细胞反应高于C/C基因型患者（P = 0.019）。未观察到SRAR发生率与rs3761547A/G或rs2232365 A/G之间存在显著关联。感染并发症和总体生存率与FOXP3 SNP无关。结论：我们的研究结果表明，FOXP3 SNP rs3761548 A/C可能是肝移植后SRAR的一个易感因素。（《移植与临床实践》2017；1：406 - 420）
