Sarwal Minnie, Chua Mei-Sze, Kambham Neeraja, Hsieh Szu-Chuan, Satterwhite Thomas, Masek Marilyn, Salvatierra Oscar
Department of Pediatrics, Stanford University, Stanford, Calif, USA.
N Engl J Med. 2003 Jul 10;349(2):125-38. doi: 10.1056/NEJMoa035588.
The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment.
We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles.
We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001).
Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection.
急性排斥反应的病因和临床过程各不相同，基于现有的临床、病理和基因标志物无法可靠地预测移植肾的预后。我们推测，先前未被认识到的分子异质性可能是急性肾移植排斥反应临床过程及其对治疗反应变异性的部分原因。
我们使用DNA微阵列对正常和功能异常的移植肾活检样本中的基因表达模式进行了系统研究。采用探索性和监督性生物信息学方法相结合的方式对这些图谱进行分析。
我们发现与急性排斥反应、药物肾毒性作用、慢性移植肾肾病和正常肾脏相关的基因表达模式存在一致差异。与急性排斥反应相关的基因表达模式提示至少存在三种可能不同的急性排斥反应亚型，这些亚型在光学显微镜下无法区分，但在免疫激活和细胞增殖方面存在差异。由于基因表达模式表明免疫浸润成分存在实质性差异，我们使用免疫组织化学染色进一步定义这些亚型。该分析揭示了密集的CD20 + B细胞浸润与临床糖皮质激素抵抗（P = 0.01）和移植肾丢失（P < 0.001）之间存在显著关联。
基因表达模式的系统分析为肾移植排斥反应的生物学和发病机制提供了一个窗口。在传统组织学分析中无法区分的急性排斥反应患者的活检样本显示出基因表达的广泛差异，这与免疫和细胞特征及临床过程的差异相关。活检样本中B细胞密集簇的存在与严重的移植肾排斥反应密切相关，提示浸润的B细胞在急性排斥反应中起关键作用。
