Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice
Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice
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DOI：
10.1172/jci42304
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Nahrendorf, Matthias
中科院分区：
文献类型：
--
作者：
Swirski, Filip K.;Wildgruber, Moritz;Nahrendorf, Matthias
心脏移植受者的移植排斥率很高。临床上显著的心脏移植排斥反应的发生和进展目前通过连续活检来监测，但这种方法是高度侵入性的并且缺乏敏感性。在这里，我们已经开发了我们认为是一种新的技术来测量器官排斥反应的非侵入性，涉及到组织浸润性白细胞作为诊断成像的生物标志物来源的探索。具体而言，我们分析了小鼠心脏移植模型中的骨髓反应，目的是定义和验证移植物排斥反应的成像特征。促进炎症的Ly-6C（hi）单核细胞在同种异体移植物中逐渐积累，但在同种异体移植物中仅短暂积累。有助于缓解炎症的Ly-6C（lo）单核细胞没有积累，尽管它们构成了同种移植物中少数剩余单核细胞的大部分。同种异体移植物中Ly-6C（hi）单核细胞的持续存在促使我们筛选Ly-6C（hi）单核细胞相关的成像标记物。低密度阵列数据显示，Ly-6C（hi）单核细胞表达的髓过氧化物酶（MPO）水平比Ly-6C（lo）单核细胞高10倍。MPO激活Gd螯合物的MPO非侵入性磁共振成像显示，在排斥的同种异体移植物中，但在同种异体移植物或MPO缺陷的同种异体移植物受体中，空间上定义的T1加权信号。流式细胞术、酶谱和组织学通过将MPO活性定位于Ly-6C（hi）单核细胞和中性粒细胞来验证该方法。因此，髓过氧化物酶成像是一种潜在的替代目前的侵入性临床标准，移植监测。
Rates of graft rejection are high among recipients of heart transplants. The onset and progression of clinically significant heart transplant rejection are currently monitored by serial biopsy, but this approach is highly invasive and lacks sensitivity. Here, we have developed what we believe to be a new technique to measure organ rejection noninvasively that involves the exploration of tissue-infiltrating leukocytes as biomarker sources for diagnostic imaging. Specifically, we profiled the myeloid response in a murine model of heart transplantation with the aim of defining and validating an imaging signature of graft rejection. Ly-6C(hi) monocytes, which promote inflammation, accumulated progressively in allografts but only transiently in isografts. Ly-6C(lo) monocytes, which help resolve inflammation, did not accumulate, although they composed the majority of the few remaining monocytes in isografts. The persistence of Ly-6C(hi) monocytes in allografts prompted us to screen for a Ly-6C(hi) monocyte-associated imaging marker. Low-density array data revealed that Ly-6C(hi) monocytes express 10-fold higher levels of myeloperoxidase (MPO) than Ly-6C(lo) monocytes. Noninvasive magnetic resonance imaging of MPO with an MPO-activatable Gd-chelate revealed a spatially defined T1-weighted signal in rejected allografts but not in isografts or MPO-deficient allograft recipients. Flow cytometry, enzymography, and histology validated the approach by mapping MPO activity to Ly-6C(hi) monocytes and neutrophils. Thus, MPO imaging represents a potential alternative to the current invasive clinical standard by which transplants are monitored.