Genomics of Chronic Rejection

We hypothesized that T cell-mediated immune mechanisms play a role in two conditions; 1: donor-specific antibody (DSA) negative transplant glomerulopathy (TGP) and 2: interstitial fibrosis and tubular atrophy (IFTA) with inflammation (i>0). We investigated gene expression profiles of those biopsies compared to biopsies with antibody-mediated rejection(ABMR) and to biopsies with non-specific IFTA and no inflammation. DSA negative TGP and IFTA with inflammation biopsies have a unique molecular signature distinct to that seen in biopsies with ABMR and IFTA without inflammation with significant expression of cytotoxic and regulatory T cells. 101 biopsies were studied using Affymetrix HuGene 1.0 ST expression arrays; 16 with normal biopsy findings (G1), 33 with a diagnosis of chronic antibody-mediated rejection (cAMR), 17 with chronic T-Cell mediated rejection and IFTA (TCMR_IFTA), 10 with T-Cell mediated rejection without DSA (TCMR_DSA-), 12 with pure IFTA (IFTA), and 13 with DSA and IFTA (DSA_IFTA).

本研究提出如下假说：T细胞介导的免疫机制在两种病理状态中发挥关键作用：1. 供体特异性抗体（donor-specific antibody, DSA）阴性移植性肾小球病（transplant glomerulopathy, TGP）；2. 伴炎症的间质纤维化伴肾小管萎缩（interstitial fibrosis and tubular atrophy, IFTA，炎症评分i>0）。为验证该假说，本研究对上述两类病理状态的活检样本进行基因表达谱分析，并以抗体介导的排斥反应（antibody-mediated rejection, ABMR）样本、非特异性IFTA且无炎症的活检样本作为对照。研究结果显示，DSA阴性TGP及伴炎症的IFTA活检样本具有独特的分子特征：其与ABMR样本及无炎症IFTA样本的分子特征存在显著差异，且细胞毒性T细胞与调节性T细胞的表达水平显著上调。本研究共纳入101例移植活检样本，采用Affymetrix HuGene 1.0 ST表达芯片进行基因表达检测，各组样本构成如下：16例活检结果正常的样本（G1组）、33例慢性抗体介导的排斥反应（chronic antibody-mediated rejection, cAMR）样本、17例伴IFTA的慢性T细胞介导排斥反应（TCMR_IFTA）样本、10例无DSA的T细胞介导排斥反应（TCMR_DSA-）样本、12例单纯IFTA（IFTA）样本，以及13例伴DSA的IFTA（DSA_IFTA）样本。