Background

The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new “Minor” category characterized by low-level inflammation in non-rejecting biopsies.

Methods

Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).

Results

Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.

Conclusions

Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

中文翻译：

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目前被诊断为无排斥的许多心脏移植活检具有轻微的分子抗体介导的排斥相关变化

背景

分子显微镜 (MMDx) 系统将心脏移植心内膜心肌活检分为无排斥 (NR)、早期损伤、T 细胞介导 (TCMR)、抗体介导 (ABMR)、混合和可能排斥（可能 TCMR、可能 ABMR ）。尚未描述 NR 活检中的排斥样基因表达模式。我们使用更大的数据集扩展了 MMDx 方法，以定义一个新的“次要”类别，其特征是非排斥活检中的低水平炎症。

方法

使用来自先前研究的 MMDx 标准，使用排斥相关转录物 (RAT) 的微阵列表达在 1,320 例活检（645 名患者）中评估了分子排斥。在这些活组织检查中，819 例为 NR。1,320 个数据集中的新原型分析模型将 NR 分为 NR-Normal (N = 462) 和 NR-Minor (N = 359)。

结果

与 NR-Normal 相比，NR-Minor 更常见于组织学 TCMR1R，供体特异性抗体 (DSA) 的患病率更高。DSA 阳性呈梯度增加：NR-正常 24%；NR-次要 34%；可能的 ABMR 42%；ABMR 66%。区分 NR-Minor 和 NR-Normal 的前 20 个转录物都是 ABMR 相关的和/或 IFNG 可诱导的，并且还表现出从 NR-Normal 到 ABMR 的表达增加梯度。在随机森林分析中，TCMR 和早期损伤与 LVEF 降低和移植物丢失增加有关，但 NR-Minor 和 ABMR 评分与此无关。令人惊讶的是，具有 MMDx ABMR 的心脏显示出相对较少的移植物丢失。

结论

目前通过组织学或分子评估诊断为 NR 的许多心脏移植物的 ABMR 相关和 IFNG 诱导的转录物有轻微增加，与 DSA 阳性和轻度组织学炎症相关。这些结果表明，与先前估计的相比，低水平 ABMR 相关的分子应激可能在更多的心脏中起作用。(ClinicalTrials.gov #NCT02670408)。