Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease.
Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease.
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DOI：
10.1016/j.bbmt.2013.06.007
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发表时间：
2013-09
影响因子：
4.3
通讯作者：
Gumperz, Jenny E.
中科院分区：
文献类型：
--
作者：
Lockridge, Jennifer L.;Zhou, Ying;Becker, Yusof A.;Ma, Shidong;Kenney, Shannon C.;Hematti, Peiman;Capitini, Christian M.;Burlingham, William J.;Gendron-Fitzpatrick, Annette;Gumperz, Jenny E.
慢性移植物抗宿主病（cGVHD）是长期造血干细胞（HSC）移植成功的重要障碍。很难开发出有效的cGVHD治疗方法，部分原因是缺乏能够概括临床cGVHD中观察到的多器官病理的动物模型。在这里，我们分析了移植了人类胚胎造血干细胞和植入了人类胎儿胸腺和肝脏碎片的免疫缺陷小鼠的病理情况。从移植后通常晚于100天的时间点开始，小鼠出现疾病迹象，包括含有人类T细胞、B细胞和巨噬细胞的多器官细胞浸润，肺和肝脏等部位纤维化，皮肤增厚并伴有脱发。延迟或降低HSC移植效率的实验操作不会影响疾病表现的时间或进展，这表明该模型中的病理更多地由与移植的人类胸腺类器官相关的因素驱动。疾病进展通常伴随着胸腺类器官的广泛纤维化和退化，疾病严重程度与Foxp3+胸腺细胞的频率呈负相关。因此，人类胸腺组织可能提供具有致病潜力的T细胞，但胸腺类器官中Tregs的产生可能有助于在类似cGVHD的病理最终发展之前控制这些细胞。因此，该模型为研究与人类胸腺事件相关的疾病病理生理学，以及评估对抗人类免疫细胞产生的多器官纤维化病理的治疗策略提供了一个新的系统。
Chronic Graft versus Host Disease (cGVHD) is a significant roadblock to long-term hematopoeitic stem cell (HSC) transplantation success. Effective treatments for cGVHD have been difficult to develop, in part because of a paucity of animal models that recapitulate the multi-organ pathologies observed in clinical cGVHD. Here we present an analysis of the pathology that occurs in immunodeficient mice engrafted with human fetal HSCs and implanted with fragments of human fetal thymus and liver. Starting at timepoints generally later than 100 days post-transplantation, the mice developed signs of illness, including multi-organ cellular infiltrates containing human T cells, B cells and macrophages, fibrosis in sites such as lungs and liver, and thickened skin with alopecia. Experimental manipulations that delayed or reduced the efficiency of the HSC engraftment did not affect the timing or progression of disease manifestations, suggesting that pathology in this model is driven more by factors associated with the engrafted human thymic organoid. Disease progression was typically accompanied by extensive fibrosis and degradation of the thymic organoid, and there was an inverse correlation of disease severity with the frequency of Foxp3+ thymocytes. Hence, the human thymic tissue may contribute T cells with pathogenic potential, but the generation of Tregs in the thymic organoid may help to control these cells before pathology resembling cGVHD eventually develops. This model thus provides a new system to investigate disease pathophysiology relating to human thymic events, as well as to evaluate treatment strategies to combat multi-organ fibrotic pathology produced by human immune cells.
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影响因子：
13.5
作者：
McDonald, George B.
通讯作者：
McDonald, George B.
影响因子：
2.7
作者：
Rajesh D;Zhou Y;Jankowska-Gan E;Roenneburg DA;Dart ML;Torrealba J;Burlingham WJ
通讯作者：
Burlingham WJ
影响因子：
56.9
作者：
MCCUNE, JM;NAMIKAWA, R;WEISSMAN, IL
通讯作者：
WEISSMAN, IL
DOI：
10.1038/nri3212
发表时间：
2012-05-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.7
作者：
Li, Qing;Zhai, Zhimin;Wang, Yiping
通讯作者：
Wang, Yiping