Transcriptome analysis reveals heterogeneity in the injury response of kidney transplants
Transcriptome analysis reveals heterogeneity in the injury response of kidney transplants
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DOI：
10.1111/j.1600-6143.2007.01980.x
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发表时间：
2007-11-01
影响因子：
8.8
通讯作者：
Halloran, P. F.
中科院分区：
文献类型：
--
作者：
Famulski, K. S.;Broderick, G.;Halloran, P. F.
我们研究了小鼠肾移植中应激和损伤增加的转录本，重点是实质细胞中增加的转录本-损伤和修复诱导的转录本（IRIT）。我们比较了四种类型的应激肾：同系移植肾、同种异体移植肾、同种异体移植小鼠的宿主肾和缺血性急性肾小管坏死（ATN）的非移植肾。在排除与浸润细胞和干扰素-γ诱导的转录本相关的转录本后，我们在同种移植物中定义了790个IRIT。IRIT在时间和机制上具有显著的异质性。有些在宿主和供体肾中增加，反映了全身影响（创伤、麻醉）。大多数反映了局部应力，类似于ATN的变化，尽管缺乏ATN组织病理学。IRIT表达模式的数学分解证实了异质性，将IRIT变化分成组分子集，早期峰值（第1天）显示全身效应，晚期峰值类似于ATN，表现出Tgf-ss 1效应并重现胚胎发育。在同种异体移植物中，IRIT最初与同种异体移植物相似，但由于同种异体损伤而不同。IRIT的同种异体诱导是T细胞依赖性的，但穿孔素颗粒酶的独立性，与迟发型超敏反应兼容。同种异体反应显著地和选择性地增加了晚期IRIT，但不是IRIT的早期峰值，表明排斥反应触发类似于ATN的实质反应。
We studied the transcripts that are increased by stress and injury in mouse kidney transplants, focusing on transcripts increased in parenchymal cells-injury and repair-induced transcripts (IRITs). We compared four types of stressed kidneys: isografts, allografts, host kidneys of mice with isografts and nontransplant kidneys with ischemic acute tubular necrosis (ATN). After excluding transcripts associated with infiltrating cells and interferon-gamma-induced transcripts, we defined 790 IRITs in isografts. IRITs were remarkably heterogeneous in timing and mechanisms. Some were increased in host as well as donor kidneys, reflecting systemic influences (wounding, anesthetic). Most reflected local stress, resembling changes in ATN despite the lack of ATN histopathology. Mathematical decomposition of IRIT expression patterns confirmed heterogeneity, separating IRIT changes into component subsets, with an early peak (day 1) showing systemic effects and late peaks that resembled ATN, manifested Tgf-ss 1 effects and recapitulated embryonic development. In allografts IRITs were initially similar to isografts but diverged due to allogeneic injury. The allospecific induction of IRITs was T-cell-dependent but perforin-granzyme-independent, compatible with delayed type hypersensitivity. The alloresponse strikingly and selectively increased the late IRITs but not the IRITs that peak early, indicating that rejection triggers parenchymal responses similar to those in ATN.