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.
|Cabrera, Susanne M; Chen, Yi-Guang; Hagopian, William A et al. (2016) Blood-based signatures in type 1 diabetes. Diabetologia 59:414-25|
|Presa, Maximiliano; Chen, Yi-Guang; Grier, Alexandra E et al. (2015) The Presence and Preferential Activation of Regulatory T Cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T Cell Effectors into NSG versus NOD-scid Mice. J Immunol 195:3011-9|
|Chen, Yi-Guang; Forsberg, Matthew H; Khaja, Shamim et al. (2014) Gene targeting in NOD mouse embryos using zinc-finger nucleases. Diabetes 63:68-74|
|Chen, Yi-Guang; Cabrera, Susanne M; Jia, Shuang et al. (2014) Molecular signatures differentiate immune states in type 1 diabetic families. Diabetes 63:3960-73|
|Chen, Y G; Mordes, J P; Blankenhorn, E P et al. (2013) Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes. Genes Immun 14:387-400|
|Tsaih, S W; Khaja, S; Ciecko, A E et al. (2013) Genetic control of murine invariant natural killer T cells maps to multiple type 1 diabetes regions. Genes Immun 14:380-6|
|Stolp, Jessica; Chen, Yi-Guang; Cox, Selwyn L et al. (2012) Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice. J Immunol 189:1406-17|
|Chen, Y-G; Tsaih, S-W; Serreze, D V (2012) Genetic control of murine invariant natural killer T-cell development dynamically differs dependent on the examined tissue type. Genes Immun 13:164-74|
|Chen, Yi-Guang; Scheuplein, Felix; Driver, John P et al. (2011) Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice. J Immunol 186:4278-84|
|Driver, John P; Chen, Yi-Guang; Zhang, Weidong et al. (2011) Unmasking genes in a type 1 diabetes-resistant mouse strain that enhances pathogenic CD8 T-cell responses. Diabetes 60:1354-9|
Showing the most recent 10 out of 11 publications