SUPPRESSION OF MULTIPLE SCLEROSIS LIKE DISEASE IN RHESUS MONKEYS

抑制恒河猴的多发性硬化症样疾病

• 批准号: 6277354
• 负责人: ARTHUR MALLEY
• 金额: $ 5.66万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6277354
• 关键词: Mammalia; Primates; animal tissue; disease /disorder prevention /control; immunology; inflammation; lymphatic system; magnetic resonance imaging; nervous system

Rhesus monkeys were immunized with bovine myelin basic protein (MBP) and M. tuberculosis H37RA in Freund's Complete Adjuvant. Controls (5/5) developed multiple sclerosis (MS)-like clinical symptoms within 20 days after immunization and were euthanized 3-5 days later. Magnetic resonance imaging and necropsy examination confirmed the presence of MS lesions in the brain and other regions of the central nervous system. Test animals treated orally with varying doses of the synthetic co-polymer Copaxone (COP-1) showed significantly reduced MS-like clinical symptoms. Peripheral blood and cerebral spinal fluid (CSF) lymphocytes were analyzed by flow cytometry to determine shifts in CD4+CD45RA+ T cells, programmed cell death and the presence of activated T cells. Plasma samples were examined by enzyme-linked immunoassay for MBP-specific IgG and IgA antibodies and T suppressor factors. 3H-thymidine incorporation was used as a measure of antigen-induced lymphocyte proliferation. Control and test animals made significant levels of MBP-specific IgG and IgA. CSF lymphocytes of controls showed an increase in the number (>50) of CD4+CD45RA- T cells one week before the onset of clinical symptoms. In contrast, lymphocytes from test animals treated with COP-1 showed a significant increase in CD4+CD45RA+ T cells, suggesting the presence of T suppressor cells. Analysis of plasma collected at various times during these studies indicate that animals treated with COP-1 produced significant levels of MBP-specific T suppressor factors. Plasma from control animals lacked MBP-specific T suppressor factors. Antigen-induced proliferation studies showed that lymphocytes from control and test animals exhibited no proliferation when cultures were pulsed with MBP, but these cells showed strong proliferation when cultured with Con A. These, studies in consort with strong positive skin tests to a purified protein derivative of H37RA (PPD), strongly suggest that the observed suppression of clinical symptoms is not due to the lack of IL-2 (anergy) or apoptosis.

用牛髓鞘碱性蛋白免疫恒河猴 (MBP)和弗氏完全佐剂中的结核分枝杆菌H37RA。 对照组(5/5)发展为多发性硬化症(MS)样临床 在免疫后20天内出现症状，并被安乐死3-5次 几天后。磁共振成像和尸检 确认在大脑和其他区域存在多发性硬化症病变 中枢神经系统。实验动物口服不同剂量的 合成的共聚物Copaxone(COP-1)的剂量显示 显著减轻MS样临床症状。 外周血和脑脊液(CSF)淋巴细胞 用流式细胞仪分析以确定CD4+CD45RA+T细胞的变化， 程序性细胞死亡和活化T细胞的存在。电浆 用酶联免疫分析法检测样本中的MBP特异性 免疫球蛋白和免疫球蛋白A抗体与T细胞抑制因子~3H-胸腺嘧啶核苷 参入率被用作抗原诱导的淋巴细胞的衡量标准 扩散。 对照组和试验组动物的MBP水平显著高于对照组。 免疫球蛋白和免疫球蛋白A。对照组的脑脊液淋巴细胞明显高于对照组。 发病前一周的CD4+CD45RA-T细胞数量(&gt；50) 临床症状。相比之下，来自实验动物的淋巴细胞 与COP-1相比，CD4+CD45RA+T细胞显著增加， 提示存在T抑制细胞。血浆的分析 在这些研究期间的不同时间收集的数据表明，动物 经COP-1处理后，MBP特异性T细胞显著增加 抑制因素。对照动物的血浆缺乏MBP特异性T细胞 抑制因素。抗原诱导的增殖研究表明 来自对照和实验动物的淋巴细胞没有表现出增殖。 当培养细胞被MBP冲击时，这些细胞表现出很强的 在与ConA一起培养时增殖，这些研究与 H37RA纯化蛋白衍生物的强阳性皮肤试验 (PPD)，强烈表明观察到的临床抑制 症状不是由于缺乏IL-2(无能)或细胞凋亡。