GENERATION OF A NON-HUMAN PRIMATE MODEL TYPE

尽管近亲繁殖的1型糖尿病啮齿动物模型在研究自身免疫破坏胰腺β细胞的基本机制方面具有宝贵的价值，但它们与人类的疾病有很大的不同，也不能准确反映人类病情的复杂性。建立非人类灵长类动物1型糖尿病模型具有重要意义，该模型具有与人类疾病相同的显著特征，可用于开发适用于人类的免疫治疗方法。这个试点R-21项目的目标是在一种非人类灵长类动物，即普通狨猴身上开发一种人类1型糖尿病模型。该方法是使用佐剂和疫苗诱导对人类疾病中的两种主要自身抗原GAD65和IA2的自身免疫，这些佐剂和疫苗已被证明在猴子中产生强大的Th1型CD4+和细胞毒性T细胞反应。First Aim验证了一种假设，即用编码GAD65和IA2的dna疫苗和/或纯化GAD65和IA2蛋白的佐剂免疫狨猴，会导致侵袭性胰岛素和1型糖尿病。《第二目标》分为两部分。如果Aim 1中使用的方法成功产生侵袭性胰岛素和β细胞破坏，Aim 2a将优化诱导糖尿病的方案并研究疾病发展机制。如果Aim 1中产生的免疫反应没有导致侵袭性胰岛素炎和β细胞破坏，Aim 2b将在免疫/疫苗接种实验中研究细胞因子和β细胞损伤增强胰腺归巢和破坏性胰岛素炎和糖尿病发展的能力。这两个目标将共同深入探索利用现有的知识、试剂和技术在狨猴身上产生一种新型1型糖尿病模型的可行性。

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.