AUTOREACTIVE T CELLS IN THE NOD MOUSE

描述(改编自《调查员摘要》)：调查员 建议继续她对T细胞的描述，这些T细胞负责 NOD小鼠IDDM的启动。在之前的研究中，调查员 已经从糖尿病NOD小鼠身上获得了几个CD4+T细胞克隆。其中两个 这些克隆被标记为BDC-2.5和BDC-6.9，对β颗粒膜起反应 抗原，并根据其诱发疾病的能力而不同 转移到NOD-SCID小鼠体内。BDC-6.9 T细胞可以单独导致疾病， 而BDC-2.5需要NOD糖尿病患者CD8+细胞的共同转移 脾可以致病。当前的应用程序侧重于使用 这些TCR用于开发转基因小鼠作为表征 IDD的发病机制。调查员有三个具体目标：1)生产 携带这些受体的TCR转基因小鼠在NOD背景下。这一目标 还建议用以下方法来表征这些菌株的基本表型 TCR表达与疾病发生率的关系。2)调查TCR 转基因小鼠作为自身免疫性疾病的免疫调节模型。 这些研究将探讨如何调节自身反应性的问题， 通过表征细胞间的相互作用和调节特性 TCR-TG小鼠体内促糖尿病T细胞的研究这些实验将解决 TCR-TG对NOD-SCID小鼠CD8细胞作用的研究 并将评估TCR-TG小鼠的Th1/Th2平衡。最后， 调查人员将研究协议的特点和要求，以 诱导小鼠对β颗粒蛋白抗原特异性耐受的尝试 采用迁移模式。3)研究其他遗传因素的影响 对TCR-TG小鼠疾病的贡献。这些研究将 描述MHC基因(D和A-asp转基因的E)和 选择非MHC基因组区间对TCR-TG糖尿病易感性的影响 老鼠。

DESCRIPTION (Adapted from Investigator's abstract): The investigator proposes to continue her characterization of the T-cells responsible for the initiation of IDDM in the NOD mouse. In previous studies, the investigator has obtained several CD4+ T-cell clones from diabetic NOD mice. Two of these clones, denoted BDC-2.5 and BDC-6.9, respond to beta granule membrane antigens and vary with respect to their capacity to induce disease on transfer into NOD-scid mice. BDC-6.9 T-cells could cause disease alone, while BDC-2.5 required the co-transfer of CD8+ cells from NOD diabetic spleens to cause disease. The current application focuses on the use of these TCR to develop transgenic mice as tools for the characterization of IDD pathogenesis. The investigator has three specific aims: 1) To produce TCR transgenic mice bearing these receptors on the NOD background. This aim also proposes to characterize the basic phenotypes of these strains with respect to TCR expression and disease incidence. 2) To investigate the TCR transgenic mouse as a model of immunoregulation of autoimmune disease. These studies would approach questions of how autoreactivity is regulated, by characterizing the cellular interactions and regulatory properties of the diabetogenic T-cells in the TCR-Tg mice. These experiments would address the role of CD8 cells by transfer studies into NOD-scid mice with the TCR-Tg T-cells and would assess Th1/Th2 balances in the TCR-Tg mice. Finally, the investigator will study the features and requirements of protocols to attempt to induce antigen-specific tolerance to beta-granule proteins in an adoptive transfer model. 3) To investigate the effects of other genetic contributions to disease in the TCR-Tg mouse. These studies will characterize the effect of MHC genes (E of d and A-asp transgenics) and selected non-MHC genomic intervals, on the diabetes susceptibility of TCR-Tg mice.