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 i s 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.
