GENERATION OF A NONHUMAN PRIMATE MODEL TYPE

非人类灵长类动物模型类型的生成

• 批准号: 6053750
• 负责人: STEINUNN BAEKKESKOV
• 金额: $ 14.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6053750
• 关键词: Callithricidae; antigen antibody reaction; autoantigens; cellular immunity; cytokine; diabetes mellitus therapy; disease /disorder model; drug design /synthesis /production; immunotherapy; insulin dependent diabetes mellitus; model design /development; tissue /cell culture; vaccine development; vector vaccine

Although inbred rodent models of type 1 diabetes have been invaluable in studying basic mechanisms of autoimmune destruction of pancreatic beta cells, they differ in significant ways from the disease in man and also do not accurately reflect the complexities of the human condition. It is important to develop a non-human primate model of type 1 diabetes, which shares significant characteristics with the human disease, and can be used to develop methods of immune therapy applicable to humans. The goal of this pilot R-21 project is to develop a model for human type 1 diabetes in a non-human primate, the common marmoset Callithrix jacchus. The approach is to induce autoimmunity to two major autoantigens in the human disease, GAD65 and IA2, using adjuvants and vaccines which have been shown to generate powerful Th1 type CD4+ and cytotoxic T cell responses in monkeys. The First Aim tests the hypothesis that immunization of marmosets with DNA-vaccines encoding GAD65 and IA2 and/or purified GAD65 and IA2 proteins in adjuvants, results in invasive insulitis and type 1 diabetes. The Second Aim is divided in two parts. If the approach used in Aim 1 succeeded in generating invasive insulitis and beta cell destruction, Aim 2a will optimize the protocols for inducing diabetes and study mechanism of disease development. If the immune response generated in Aim 1 did not result in invasive insulitis and beta cell destruction, im 2b will study the ability of cytokines and beta cell injury to enhance homing to the pancreas and development of destructive insulitis and diabetes in immunization/vaccination experiments. Together the two aims will explore in depth the feasibility of generating a novel model of type 1 diabetes in the marmoset monkey using current knowledge, reagents, and techniques.

尽管近交系啮齿动物模型在研究胰腺β细胞自身免疫性破坏的基本机制方面具有非常宝贵的价值，但它们与人类疾病有显著的不同，并且也不能准确反映人类疾病的复杂性。重要的是开发1型糖尿病的非人灵长类动物模型，其与人类疾病具有显著特征，并且可用于开发适用于人类的免疫治疗方法。这个试验性R-21项目的目标是在非人类灵长类动物中开发人类1型糖尿病模型，即普通的绒猴Callithrix jacchus。该方法是使用佐剂和疫苗诱导对人类疾病中两种主要自身抗原GAD 65和IA 2的自身免疫，这些佐剂和疫苗已显示在猴中产生强大的Th 1型CD 4+和细胞毒性T细胞应答。第一个目标测试了这样的假设：用编码GAD 65和IA 2的DNA疫苗和/或佐剂中的纯化GAD 65和IA 2蛋白免疫绒猴，会导致侵袭性胰岛炎和1型糖尿病。第二个目标分为两部分。如果目标1中使用的方法成功地产生侵袭性胰岛炎和β细胞破坏，目标2a将优化诱导糖尿病的方案并研究疾病发展的机制。如果目标1中产生的免疫应答未导致侵袭性胰岛炎和β细胞破坏，则im 2b将研究细胞因子和β细胞损伤在免疫/疫苗接种实验中增强胰腺归巢和破坏性胰岛炎和糖尿病发展的能力。这两个目标将共同深入探讨利用现有知识、试剂和技术在绒猴中产生1型糖尿病新模型的可行性。