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(T1D)是由T细胞介导的产生胰岛素的胰岛β细胞破坏所致。以前使用NOD小鼠模型的研究表明，糖尿病T细胞的发展部分是由于树突状细胞(DC)的耐受功能缺陷所致。反过来，NOD DC的有缺陷的耐受活性与iNKT细胞的异常有关，iNKT细胞也是这种菌株的特征。用iNKT细胞活化剂α-半乳糖基神经酰胺(GalCer)治疗NOD小鼠，T1D被抑制。初步数据表明，GalCer激活的iNKT细胞分泌一种可溶性因子(S)，促进耐受性DC在胰腺淋巴结(PLN)中的分化和积聚，从而删除或灭活致糖尿病T细胞，从而产生保护作用。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，这种因子通过假想地诱导耐受树突状细胞来抑制T1D。然而，在iNKT细胞衍生的耐受因子(S)被考虑用于预防人类T1D之前，确定其诱导机制和生物学功能范围也是至关重要的。因此，本提案的总体目标是进一步阐明iNKT-DC轴在NOD小鼠T1D发育中的作用，希望这些信息最终可能有助于设计一种新的方法或鉴定一种药物来预防人类的这种疾病。目标1和2是确定什么iNKT细胞子集可以将DC驱动到T1D保护状态，以及这一过程是如何启动的。目的3是确定被激活的iNKT细胞条件下的DC是否必须定量增加PLN以抑制NOD小鼠的T1D，并进一步确定它们是如何做到这一点的。T1D是一种受基因控制的疾病。因此，利用转基因节点进行的实验是研究这种疾病的重要途径。杰克逊实验室为我提供了一个更好的环境，通过使用大量宝贵的小鼠资源来获得更多的哺乳动物遗传学知识。我的长期职业目标是成为一名独立的研究人员，为我们理解自身免疫性疾病，特别是T1D做出重大贡献，并设计新的方法来预防或治疗这些疾病。我相信，这份《独立之路》应用程序中描述的程序将通过提高我设计实验、发表和展示原创研究成果以及与其他研究人员建立合作关系的能力来帮助我实现这一目标。与公共健康相关：自身免疫性T1D是产生胰岛素的胰岛β细胞自身免疫破坏的结果。这项建议的总体目标是进一步确定如何通过一种最终可能用于在人类中抑制这种疾病的药物来纠正NOD小鼠模型中T1D免疫耐受诱导方面的缺陷。

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.