Role of the iNKT-Dendritic Cell Axis in Type 1 Diabetes in NOD Mice

描述（由申请人提供）： 自身免疫性1型糖尿病（T1 D）是由T细胞介导的对产生胰岛素的胰腺β细胞的破坏引起的。先前使用NOD小鼠模型的研究表明，致糖尿病性T细胞的形成部分是由于树突状细胞（DC）致耐受性功能的缺陷。反过来，NOD DC的缺陷性致耐受性活性与iNKT细胞中的异常相关，iNKT细胞也表征了该菌株。在用iNKT细胞活化剂α-半乳糖神经酰胺（GalCer）处理的NOD小鼠中，T1 D被抑制。初步数据表明来自GalCer活化的iNKT细胞的保护结果，所述iNKT细胞分泌可溶性因子，所述可溶性因子增强致耐受性DC在胰腺淋巴结（PLN）中的分化和积累，在所述淋巴结中它们随后删除或消除致糖尿病性T细胞。我的博士后导师有独立的资金来确定iNKT细胞衍生因子的身份，该因子通过诱导致耐受性DC来抑制T1 D。然而，在iNKT细胞衍生的致耐受性因子可被考虑用作预防人类T1 D的药理学试剂之前，确定其诱导机制和生物学功能范围也将是至关重要的。因此，目前提案的总体目标是进一步阐明iNKT-DC轴在NOD小鼠T1 D发展中的作用，希望这些信息最终有助于设计新方法或鉴定预防人类这种疾病的药理学药物。目的1和2是确定什么iNKT细胞亚群可以将DC驱动到T1 D保护状态以及如何启动该过程。目的3是确定由活化的iNKT细胞调节的DC是否必须定量增加PLN以抑制NOD小鼠中的T1 D，并进一步确定它们如何做到这一点。T1 D是一种基因控制的疾病。因此，使用转基因NOD股票的实验代表了一个重要的方法来研究这种疾病。杰克逊实验室为我提供了一个上级环境，通过使用大量有价值的小鼠资源来获得哺乳动物遗传学的额外知识。我的长期职业目标是成为一名独立的研究人员，为我们对自身免疫性疾病的理解做出重大贡献，特别是T1 D，并设计新的方法来预防或治疗这些疾病。我相信在这个“独立之路”应用程序中描述的程序将帮助我实现这一目标，提高我的能力，设计实验，发表和提出原创研究成果，并建立与其他研究人员的合作。与公共卫生的相关性：自身免疫性T1 D是由产生胰岛素的胰腺β细胞的自身免疫性破坏引起的。该提案的总体目标是进一步确定NOD小鼠模型中T1 D免疫耐受诱导的缺陷如何通过可能最终用于在人类中抑制这种疾病的试剂来纠正。

DESCRIPTION (provided by applicant): Autoimmune type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing pancreatic beta cells. Previous studies using the NOD mouse model indicate the development of diabetogenic T cells partly results from defects in the tolerogenic functions of dendritic cells (DCs). In turn, the defective tolerogenic activity of NOD DCs is linked to abnormalities in iNKT cells also characterizing this strain. T1D is inhibited in NOD mice treated with the iNKT cell-activating agent alpha-galactosylceramide (GalCer). Preliminary data indicate protection results from GalCer-activated iNKT cells secreting a soluble factor(s) that enhances the differentiation and accumulation of tolerogenic DCs in pancreatic lymph nodes (PLNs) where they subsequently delete or inactivate diabetogenic T cells. My postdoctoral mentor has independent funding to determine the identity of the iNKT cell derived factor that inhibits T1D by putatively inducing tolerogenic DCs. However, before the iNKT cell-derived tolerogenic factor(s) could be considered for use as a pharmacological agent to prevent T1D in humans, it will also be critical to determine its mechanism of induction and range of biological functions. Therefore, the overall goal of the current proposal is to further elucidate the role of the iNKT-DC axis in T1D development in NOD mice, with the hope that such information may ultimately aid in the design of a novel method or identification of a pharmacological agent to prevent this disease in humans. Aims 1 and 2 are to identify what iNKT cell-subset can drive DC to a T1D protective state and how this process is initiated. Aim 3 is to determine whether DCs conditioned by activated iNKT cells must quantitatively increase in PLNs to inhibit T1D in NOD mice, and further define how they do so. T1D is a genetically controlled disease. Therefore, experiments using genetically modified NOD stocks represent an important approach to study this disease. The Jackson Laboratory provides me a superior environment to gain additional knowledge of mammalian genetics by using a large collection of valuable mouse resources. My long-term career goal is to become an independent researcher who makes significant contributions to our understanding of autoimmune disorders, in particular T1D, and to design novel approaches to prevent or treat these diseases. I believe the program described in this "Pathway to Independence" application will help me achieve this goal by improving my ability to design experiments, publish and present original research results, and establish collaborations with other investigators. Relevance to Public Health: Autoimmune T1D results from autoimmune destruction of insulin-producing pancreatic beta cells. The overall goal of this proposal is to further determine how the defects in immunological tolerance induction underlying T1D in the NOD mouse model can be corrected by an agent that might ultimately be used to pharmacologically inhibit this disease in humans.