? In autoimmune diabetes, both patients with type 1 diabetes and non-obese diabetic (NOD) mice develop T and B cell responses against autoantigens expressed by insulin-producing beta cells in the islets of Langerhans of the pancreas. Our goal is to find ways of turning off these pathogenic responses. My hypothesis is that dendritic cells can be used to expand, from a polyclonal T cell repertoire in autoimmune NOD mice, islet-specific CD4+CD25+ regulatory T cells that can block the development of autoimmune diabetes. In the experiments proposed here, first DCs will be loaded with either pools of islet peptides or purified islet cells to expand functional islet-specific regulatory T cells from the lymphoid organs of NOD mice. The function of these expanded cells will be tested using in vitro suppression assays of proliferation and in vivo assays for delay or block of diabetes development. Secondly, new-onset diabetic mice will be treated with islet-specific regulatory T cells to induce tolerance, and with beta cell growth factors to restore endogenous insulin-secreting capacity. In these experiments, glucose homeostasis will be tested by both measuring blood glucose levels and a glucose tolerance test. Finally, the mechanism of action of islet-specific regulatory T cells will be studied by identifying them with a congenic marker after transfer to NOD mice. The location and protein/gene expression of the transferred cells will be assayed using flow cytometry, fluorescence microscopy, and real-time PCR. My immediate career goals are to pursue the questions outlined in this application, and to learn the new skills required in an optimal environment with excellent resources. After that, I plan to pursue an independent position where I can focus on not only basic autoimmunity research but also more translational research. My long-term scientific goal is to understand the control of self-tolerance such that autoimmunity can be controlled in an autoantigen-specific way ? ?
| Mukhopadhaya, Arunika; Hanafusa, Tadashi; Jarchum, Irene et al. (2008) Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. Proc Natl Acad Sci U S A 105:6374-9 |
| Luo, Xunrong; Tarbell, Kristin V; Yang, Hua et al. (2007) Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:2821-6 |
| Tarbell, Kristin V; Petit, Lucine; Zuo, Xiaopan et al. (2007) Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 204:191-201 |
