Zheng H X, Zeevi A, McCurry K, Schuetz E, Webber S, Ristich J, Zhang J, Iacono A, Dauber J, McDade K, Zaldonis D, Lamba J, Burckart G J
School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC-100, Los Angeles, CA 90033, USA.
Transpl Immunol. 2005 Mar;14(1):37-42. doi: 10.1016/j.trim.2004.11.001. Epub 2004 Dec 7.
Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective of this study was to evaluate the risk factors, including human multidrug resistance gene (MDR1), cytochrome P4503A5 (CYP3A5) and cytokine gene polymorphisms, associated with acute persistent rejection (APR) in lung transplant patients. One hundred and twenty-five adult lung transplant patients were studied. MDR1 G2677T, C3435T and CYP3A5 polymorphisms were assessed by direct sequencing of the polymorphic region in patient DNA. Cytokine genotyping for five cytokines was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) technique. Multivariate regression analysis was used to identify the predictors of acute persistent rejection. The dependent variable was the presence or absence of acute persistent rejection based on lung biopsies during the first postoperative year. The independent variables were MDR1 G2677T and C3435T, CYP4503A5 and cytokine polymorphisms, survival status, age, gender, survival days and HLA mismatches. The MDR1 C3435T polymorphism and age were independently associated with acute persistent rejection (p = 0.025, odds ratio = 0.29, 95% CI 0.1-0.86 and p = 0.016, odds ratio = 0.94, 95% CI 0.89-0.98, respectively). For the MDR1 C3435T polymorphism, 72% of patients with the C allele had acute persistent rejection in comparison to 52% for TT patients (p = 0.04). For age, a significant difference was found between the nonrejection group and the rejection group (mean+/-S.D. 52.1+/-11.2 vs. 44.4+/-12.3, p = 0.01). This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The major predictor of acute persistent rejection in the first postoperative year for lung transplant patients was the MDR1 C3435T genotype. This association could be due to drug resistance, altered drug disposition or other immunologic effects associated with P-glycoprotein (P-gp) function. Future prospective treatment algorithms should be developed that will incorporate the knowledge of gene polymorphisms into treatment regimens to improve the outcome following lung transplantation.
在实体器官移植中，即便接受治疗仍持续存在的排斥反应以及多次排斥发作与慢性排斥反应的发生和移植物丢失相关。然而，那些在治疗情况下仍持续产生排斥反应环境的因素目前尚不清楚。本研究的目的是评估与肺移植患者急性持续性排斥反应（APR）相关的危险因素，包括人类多药耐药基因（MDR1）、细胞色素P4503A5（CYP3A5）和细胞因子基因多态性。对125例成年肺移植患者进行了研究。通过对患者DNA中多态性区域的直接测序来评估MDR1 G2677T、C3435T和CYP3A5多态性。使用聚合酶链反应 - 序列特异性引物（PCR - SSP）技术对五种细胞因子进行细胞因子基因分型。采用多变量回归分析来确定急性持续性排斥反应的预测因素。因变量是基于术后第一年肺活检结果判断是否存在急性持续性排斥反应。自变量包括MDR1 G2677T和C3435T、CYP4503A5和细胞因子多态性、生存状态、年龄、性别、生存天数以及HLA错配情况。MDR1 C3435T多态性和年龄与急性持续性排斥反应独立相关（p = 0.025，比值比 = 0.29，95%置信区间0.1 - 0.86；p = 0.016，比值比 = 0.94，95%置信区间0.89 - 0.98）。对于MDR1 C3435T多态性，携带C等位基因的患者中有72%发生了急性持续性排斥反应，而TT患者为52%（p = 0.04）。对于年龄，未发生排斥反应组与发生排斥反应组之间存在显著差异（平均值±标准差 52.1±11.2对44.4±12.3，p = 0.01）。这是关于药物处置基因型与器官移植患者耐药性急性排斥反应相关性的首次报道。肺移植患者术后第一年急性持续性排斥反应的主要预测因素是MDR1 C3435T基因型。这种关联可能是由于耐药性、药物处置改变或与P - 糖蛋白（P - gp）功能相关的其他免疫效应。未来应制定前瞻性治疗算法，将基因多态性知识纳入治疗方案，以改善肺移植后的结局。
