Intravital Imaging of Type I Diabetes

描述（由申请人提供）：在疾病进展过程中，器官特异性自身免疫发生三个主要事件：自身反应性T细胞产生(I)，它们运输到目标器官（II），它们破坏器官（III）。1型糖尿病（T1D）是这种疾病的一个明显例子。其发病率在发达国家呈上升趋势，对T1D最有效的治疗仍然是提供胰岛素。我们一直专注于T细胞归巢到产生胰岛素的胰岛的研究，结合体内和体外方法来追踪T细胞，并寻找驱动T细胞到胰岛的分子线索。这些研究的目的是寻找阻断T细胞归巢的靶点，以治疗T1D。我们逐渐认识到，由于无法追踪T细胞攻击期间单个胰岛的命运，这一领域的进展受到了阻碍。显然，如果我们掌握了这种可能性，我们就能更快地理解T细胞浸润的规则，也能更快地跟踪T细胞消融后2个细胞的命运，并测试2个细胞再生方案。为了实现这些目标，我们提出了一个简单的解决方案：允许活体显微镜（AWIM）的腹部窗口。我们完善了这项技术，使我们能够轻松地解决与T细胞归巢和胰岛破坏/再生有关的许多问题。我们还将采用一种新的全器官成像方法来描述T1D发展过程中胰腺炎症的整体特征。为此，我们将努力实现以下具体目标。具体目标进一步描述交叉呈递在T细胞归巢中的作用。具体目标2。研究自然活化的T细胞到胰腺的归巢。

DESCRIPTION (provided by applicant): Three major events happen in organ-specific autoimmunity during disease progression: autoreactive T cells are generated (I), they traffic to the target organ (II), and they destroy the organ (III). Type 1 diabetes (T1D) is a clear example of such a disease. Its incidence is on the rise in developed countries, and the most efficient therapy for T1D is still the provision of insulin. We have been focusing on the studies of T cell homing to the insulin-producing islets, combining in vivo and in vitro approaches for tracing T cells and searching for molecular clues to what drives T cells to the islets. The goal of these studies is to find targets for blocking homing of T cells for therapeutic intervention in T1D. We came to realization that progress in the field was hampered by the inability to follow the fate of individual islets during T cell attack. Clearly, should we have had this possibility in hand, we would progress much faster in understanding the rules of T cell infiltration, and also in following the fate of 2 cells after T cell ablation and test 2 cell regeneration protocols. To achieve these goals, we came up with a simple solution: an abdominal window allowing intravital microscopy (AWIM). We perfected the technique to the point where we can comfortably address many issues related to T cell homing and islet destruction/regeneration. We also will employ a novel whole organ imaging approach to delineate the global features of inflammation in the pancreas during T1D development. Accordingly, we will pursue the following Specific Aims. Specific Aim 1. Further delineate the role of cross-presentation in homing of T cells. Specific Aim 2. Study the homing of naturally activated T cells to the pancreas. .