Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft‐versus‐host disease
Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft‐versus‐host disease
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DOI：
10.1189/jlb.0211067
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发表时间：
2011-07
影响因子：
5.5
通讯作者：
S. Zinöcker;L. Sviland;R. Dressel;B. Rolstad
中科院分区：
文献类型：
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作者：
S. Zinöcker;L. Sviland;R. Dressel;B. Rolstad
在接受异基因血细胞移植的患者中，移植物抗宿主病导致广泛的发病率和死亡率。目前缺乏可预测和可靠的GVHD标记物，但需要这些标记物来提高异体血细胞移植的安全性和可及性。我们提出了一种实验性的大鼠模型，采用清髓性全身照射和完全不匹配的主要和次要组织不合，T细胞耗尽的骨髓移植，然后延迟输注供者淋巴细胞。与单纯骨髓移植相比，这种治疗在2-6周内导致严重的aGVHD和100%的致死率。我们研究了供者白细胞亚群的重建动力学和表型，以及可能与GVHD相关的选定器官的组织病理学，目的是寻找潜在的疾病相关标记物。我们观察到主要局限于皮肤的组织学变化，基底层有退行性变化。LNS和脾呈紊乱结构，淋巴细胞显著聚集，而肠、肝和肺则正常。在检测的淋巴细胞标志物中，供者来源的CD62L+T细胞在GVHD动物中显著减少。此外，我们观察到与对照组相比，外周血中CD4+CD25hiFoxP3+Treg的耗竭。因此，这些淋巴细胞亚群在血液中的相对频率可以作为aGVHD的可获得的细胞标志物。我们认为，所建立的动物模型对确定GVHD的临床相关标志物具有指导意义，有助于提高异基因Hct的疾病诊断和治疗水平。
GVHD causes extensive morbidity and mortality in patients who receive alloHCT. Predictive and reliable markers for GVHD are currently lacking but required to improve the safety and accessibility of alloHCT. We present an experimental rat model of myeloablative total body irradiation and fully mismatched major and minor histoincompatible, T cell‐depleted BMT, followed by delayed infusion of donor lymphocytes. This treatment, in contrast to marrow transplantation alone, resulted in severe aGVHD and 100% lethality within 2–6 weeks. We investigated the reconstitution kinetics and phenotypes of donor leukocyte subpopulations as well as the histopathology of selected organs that may correlate with GVHD, with the goal to find potential disease‐related markers. We observed histological changes mainly confined to the skin, with degenerative changes in the basal layer. LNs and spleen showed deranged architecture with markedly increased accumulation of lymphocytes, whereas the gut, liver, and lungs appeared normal. Of the lymphocyte markers tested, donor‐derived CD62L+ T cells were markedly decreased in animals suffering from GVHD. Furthermore, we observed peripheral depletion of CD4+CD25hiFoxP3+ Treg, which was in contrast to controls. The relative frequency of these lymphocyte subpopulations in blood may therefore serve as accessible cellular markers of aGVHD. We propose that the animal model presented is instructive for the identification of clinically relevant markers of GVHD, which could improve disease diagnosis and management in alloHCT.