DEVELOPMENT OF AN ANIMAL MODEL FOR HEMOLYTIC UREMIA SYNDROME (HUS) WITH NONHUMAN PRIMATES

非人灵长类溶血性尿毒症综合征 (HUS) 动物模型的开发

• 批准号: 09480248
• 负责人: YOSHIKAWA Yasuhiro
• 金额: $ 7.81万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09480248/
• 关键词: KEY MORDS; cynomolgus monkey; African green monkey; Vero toxins; O-157; VT1; VT2; HUS model; ceramid trihexose; セラシド・トリヘキソース; CTH; VT1,VT2; レセプター; セラミド・トリヘキソース

To develop an animal model for hemolytic uremia syndrome (HUS) using non-human primates, Cercopithecine monkeys such as African green monkeys (Cercopithecus aetiopus) and cynomolgus monkeys (Macaca fascicularis) were used in this experiment. The existence of a glycolipid receptor (ceramid trihexose ; CTH) for Vero toxins (VT1, VT2) was investigated by a biochemical method with thin layer chromatography. As a result, the receptors were more abundantly expressed in a cynomolgus monkey than an African green monkey and they localized mainly in the kidneys, spleen, bone marrow and lungs. Immunohistological studies by the use of a monoclonal antibody recognizing the CTH revealed that it was expressed densely in the mucosal epithelial cells of the small intestine, glomerulus and renal tubules in the kidneys and vascular endothelial cells in the medulla of the spleen and small blood vessels in the whole body. In the in vivo study, 24〜48hrs after Vero toxins (VT1 or VT2) injection, cynomolgus monkeys became moribund and they showed intestinal hemorrhage with thoracic fluid or ascite. Obvious thrombocytepenia, deterioration of a coagulation function and anomalies of the blood biochemical values were demonstrated. Histological examinations exhibited necrosis and severe hemorrhage in the intestinal mucosa, hemorrhage in the adrenal cortex, edematous change in the lungs, vacuolar degeneration of the vascular endothelial cells and degeneration of glomerulus and renal tubules in the kidneys, which are similar to clinicopathological lesions observed in human cases.

为了建立溶血性尿毒症综合征（HUS）的非人类灵长类动物模型，本实验以非洲绿猴（Cercopithecus aetiopus）和食环猴（Macaca fascicularis）为研究对象。采用薄层色谱法研究了Vero毒素（VT1, VT2）的糖脂受体（ceramid trihexose； CTH）的存在。结果，这些受体在食蟹猴中比非洲绿猴表达得更丰富，它们主要分布在肾脏、脾脏、骨髓和肺部。利用单克隆抗体识别CTH的免疫组织学研究显示，CTH在小肠粘膜上皮细胞、肾脏肾小球和肾小管以及脾脏髓质的血管内皮细胞和全身小血管中密集表达。在体内研究中，注射Vero毒素（VT1或VT2）后24 ~ 48h，食蟹猴死亡，出现肠道出血，胸腔积液或腹水。明显的血小板减少，凝血功能恶化和血液生化指标异常。组织学检查显示肠黏膜坏死及严重出血，肾上腺皮质出血，肺部水肿改变，血管内皮细胞空泡变性，肾脏肾小球及肾小管变性，与人临床病理病变相似。

项目成果

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