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

为了使用非人灵长类动物开发溶血性尿毒症综合征（HUS）的动物模型，在该实验中使用了猕猴，例如非洲绿色猴（Cercopithecus aetiopus）和食蟹猴（Macaca fascicularis）。用薄层层析的生化方法研究了Vero毒素（VT 1，VT 2）的糖脂受体（神经酰胺三己糖; CTH）的存在。结果表明，受体在食蟹猴中比在非洲绿色猴中更丰富地表达，并且它们主要定位于肾、脾、骨髓和肺中。通过使用识别CTH的单克隆抗体进行的免疫组织学研究表明，CTH密集表达于小肠的粘膜上皮细胞、肾脏的肾小球和肾小管以及脾脏髓质和全身小血管的血管内皮细胞中。在体内研究中，在注射Vero毒素（VT 1或VT 2）后24 - 48小时，食蟹猴出现濒死状态，并显示肠道出血伴胸腔积液或腹水。表现出明显的血小板增多、凝血功能恶化和血液生化值异常。组织学检查显示肠粘膜坏死和严重出血，肾上腺皮质出血，肺水肿，血管内皮细胞空泡变性以及肾脏肾小球和肾小管变性，这些与人类病例中观察到的临床病理学病变相似。

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.