Bernstein Daniel, Williams Gavin E, Eisen Howard, Mital Seema, Wohlgemuth Jay G, Klingler Tod M, Fang Kenneth C, Deng Mario C, Kobashigawa Jon
Department of Pediatrics (Cardiology), Stanford University, Stanford, California 94304, USA.
J Heart Lung Transplant. 2007 Dec;26(12):1270-80. doi: 10.1016/j.healun.2007.09.017.
Gene expression profiling distinguishes the absence or presence of moderate to severe grades of acute cellular rejection in cardiac allograft recipients using a 20-gene classifier. We explored the hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations.
A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier-derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner.
Mean GE scores not only differentiated Grades >or=3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (p < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and >or=3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades >or=3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade >or=3A rejection, while expression of PDCD1 or SEMA7A showed similar directional patterns without achieving statistical significance.
These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 1B according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined.
基因表达谱分析使用一个包含20个基因的分类器，可区分心脏移植受者中是否存在中度至重度急性细胞排斥反应。我们探讨了以下假设，即该排斥反应分类器也能区分各种形式的轻度排斥反应，并基于移植后的时间和病理检查结果进行了亚组分析。
对265例CARGO研究患者和714次临床病例进行事后分析，重点关注心内膜心肌活检时血样中排斥反应分类器衍生的基因表达（GE）分数之间的相关性。研究中心病理学家（中心）指定的活检分级由三位病理学家（小组）以盲法重新解读。
根据国际心脏和肺移植学会（ISHLT）1990年分级系统定义的轻度排斥反应亚组，平均GE分数不仅能区分3A级及以上与0级排斥反应（中心或小组，p<0.00001），还能区分与1A级或2级排斥反应（中心或小组，p<0.05）。相比之下，无论是中心还是小组的解读，1B级与3A级及以上的平均GE分数都没有差异。对移植后2至6个月或超过6个月的病例进行亚组分析显示，该分类器区分中度至重度排斥反应与1A级和2级轻度排斥反应的能力结果相似，但3A级及以上与1B级亚组的平均GE分数没有差异。在该分类器的11个信息基因中，MIR和WDR40的表达在1B级和3A级及以上排斥反应中均有统计学意义的增加，而PDCD1或SEMA7A的表达呈现相似的变化趋势，但未达到统计学意义。
这些数据表明，GE分数能区分中度至重度排斥反应与1A级和2级轻度排斥反应。然而，根据1990年分级系统定义为1B级的轻度排斥反应亚组，其分子特征与中度至重度排斥反应更为一致。这些数据的临床相关性仍有待确定。
