Gaur L K, Nepom G T, Lernmark A
Puget Sound Blood Center; Seattle, Washington 98104, USA.
Autoimmunity. 2001;33(2):103-14. doi: 10.3109/08916930108995995.
The potential for using macaques to create a nonhuman primate diabetic model was investigated. The significant objectives were to determine a) prognosis of STZ induced permanent beta cell destruction in nonhuman primates, and b) the potential to use STZ treated animals in a model of autoimmune diabetes by following adoptively transferred lymphocytes into MHC identical macaques. Beta cell impairment was achieved by a single intravenous, low dose (10-40 mg/kg body weight) streptozotocin injection in a majority of pigtailed macaques (Macaca nemestrina). Multiple injections, even at low doses at close intervals affected liver and kidney functions in addition to beta cell destruction. Abnormal IVGTT were observed in all streptozotocin-treated animals, in some within a week to 10 days. The fasting blood glucose levels rose from <70 mg/dl in pre-STZ stage to above 400 mg/dl in severely diabetic macaques. Histological evidence suggests loss of beta cells when animals were euthanized within two to four weeks post-STZ treatment. Near complete destruction of beta cells was observed in animals maintained longer than three months on insulin. Donor T cells from STZ-treated animals were incubated overnight with 10U/ml IL-2 and 2.5 ug/ml PHA and then injected iv into a MHC-identical non-diabetic sibling. Three weeks later a second injection of donor PMBC labeled with vital dye Cell Tracker Green was given and the animal was euthanized after 24 hours. The recipient showed labeled donor T cells in the pancreas, spleen and peripheral blood, consistent with specific homing of activated lymphocytes from the diabetic donor.
研究了使用猕猴建立非人类灵长类糖尿病模型的可能性。主要目标是确定：a）链脲佐菌素诱导的非人类灵长类动物永久性β细胞破坏的预后，以及b）通过将过继转移的淋巴细胞导入MHC相同的猕猴体内，利用链脲佐菌素处理的动物建立自身免疫性糖尿病模型的可能性。在大多数猪尾猕猴（食蟹猴）中，通过单次静脉注射低剂量（10 - 40mg/kg体重）链脲佐菌素实现β细胞损伤。多次注射，即使是低剂量且间隔很近，除了β细胞破坏外，还会影响肝脏和肾脏功能。在所有接受链脲佐菌素治疗的动物中均观察到异常的静脉葡萄糖耐量试验，有些在一周至10天内出现。空腹血糖水平从链脲佐菌素治疗前的<70mg/dl升至重度糖尿病猕猴的400mg/dl以上。组织学证据表明，在链脲佐菌素治疗后两至四周内对动物实施安乐死时，β细胞有所丢失。在接受胰岛素治疗超过三个月的动物中，观察到β细胞几乎完全被破坏。将来自链脲佐菌素处理动物的供体T细胞与10U/ml白细胞介素-2和2.5μg/ml植物血凝素一起孵育过夜，然后静脉注射到MHC相同的非糖尿病同胞体内。三周后，第二次注射用活体染料Cell Tracker Green标记的供体外周血单核细胞，24小时后对动物实施安乐死。受体的胰腺、脾脏和外周血中显示有标记的供体T细胞，这与来自糖尿病供体的活化淋巴细胞的特异性归巢一致。
