Sreekumar Raghavakaimal, Rasmussen Deborah L, Wiesner Russell H, Charlton Michael R
Transplant Center, Mayo Clinic and Foundation, Rochester, MN, USA.
Liver Transpl. 2002 Sep;8(9):814-21. doi: 10.1053/jlts.2002.35173.
Treatment of acute cellular rejection (ACR) is associated with increased viral load, more severe histologic recurrence, and diminished patient and graft survival after liver transplantation for hepatitis C virus (HCV). Recurrence of HCV may be difficult to distinguish histologically from ACR. Because the immunologic mechanisms of ACR and HCV recurrence are likely to differ, we hypothesized that ACR is associated with the expression of a specific subset of immune activation genes that may serve as a diagnostic indicator of ACR and provide mechanistic insight into the pathophysiology of ACR and recurrence of HCV. The goal of the study was to study intragraft gene expression patterns in ACR and during recurrence of HCV in HCV-infected recipients. High-density microarrays were used to determine relative intragraft gene expression in two groups of HCV-infected liver transplant recipients: four with steroid responsive ACR by Banff criteria and four age- and gender-matched HCV-infected recipients with similar necroinflammatory activity but without histological criteria for rejection (no cholangitis or endotheliitis). Immunosuppression was similar in both groups. Other etiologies of graft dysfunction were excluded by ultrasound, cholangiography, and cultures. High-quality total RNA was extracted from snap frozen liver biopsies, reverse transcribed, labeled with biotin, and fragmented according to established protocol. Twenty-five genes were relatively overexpressed, and 15 were relatively underexpressed by > or = twofold in the ACR when compared with the HCV group. ACR was most notably associated with the relative overexpression of genes associated with major histocompatibility complex I and II, insulin-like growth factor-1 expression, apoptosis induction, and T-cell activation. In HCV-infected liver transplant recipients, ACR is associated with an intragraft gene expression profile that is distinct from that seen during recurrence of HCV. These experiments provide evidence that alloimmunity, as indicated by expression of T-cell activation and apoptosis-inducing genes, is less important in recurrence of HCV than in ACR. Further studies are required to determine whether gene expression profiles, either intragraft or in serum, can be used for the diagnosis and differentiation of ACR from recurrence of HCV.
急性细胞性排斥反应（ACR）的治疗与病毒载量增加、更严重的组织学复发以及丙型肝炎病毒（HCV）肝移植后患者生存率和移植物存活率降低相关。HCV复发在组织学上可能难以与ACR区分。由于ACR和HCV复发的免疫机制可能不同，我们推测ACR与免疫激活基因特定子集的表达相关，这些基因可能作为ACR的诊断指标，并为ACR的病理生理学和HCV复发提供机制性见解。本研究的目的是研究HCV感染受者中ACR时和HCV复发期间移植物内的基因表达模式。使用高密度微阵列来确定两组HCV感染肝移植受者移植物内的相对基因表达：根据班夫标准有4例对类固醇有反应的ACR患者，以及4例年龄和性别匹配、具有相似坏死性炎症活动但无排斥反应组织学标准（无胆管炎或内皮炎）的HCV感染受者。两组的免疫抑制情况相似。通过超声、胆管造影和培养排除移植物功能障碍的其他病因。从速冻肝活检组织中提取高质量的总RNA，进行逆转录，用生物素标记，并按照既定方案进行片段化。与HCV组相比，ACR组有25个基因相对过表达，15个基因相对低表达超过或等于两倍。ACR最显著地与主要组织相容性复合体I和II相关基因、胰岛素样生长因子-1表达、凋亡诱导和T细胞激活的相对过表达相关。在HCV感染的肝移植受者中，ACR与移植物内基因表达谱相关，该谱与HCV复发期间所见不同。这些实验提供了证据，表明如T细胞激活和凋亡诱导基因表达所示的同种免疫在HCV复发中不如在ACR中重要。需要进一步研究以确定移植物内或血清中的基因表达谱是否可用于ACR与HCV复发的诊断和鉴别。
