Intravital Imaging of Type I Diabetes

描述(申请人提供)：在疾病进展过程中，器官特异性自身免疫过程中发生三个主要事件：产生自身反应性T细胞(I)，它们运输到目标器官(II)，它们破坏器官(III)。1型糖尿病(T1D)就是这种疾病的一个明显例子。它的发病率在发达国家呈上升趋势，而治疗T1D最有效的治疗方法仍然是提供胰岛素。我们一直专注于T细胞归巢于产生胰岛素的胰岛的研究，结合体内和体外追踪T细胞的方法，并寻找是什么驱使T细胞进入胰岛的分子线索。这些研究的目标是找到阻断T细胞归巢的靶点，用于T1D的治疗干预。我们意识到，由于无法在T细胞攻击期间跟踪单个胰岛的命运，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，我们就会更快地了解T细胞渗透的规律，并在跟踪T细胞消融后2细胞的命运和测试2细胞再生方案方面取得更大进展。为了实现这些目标，我们提出了一个简单的解决方案：允许活体内显微镜(AWIM)的腹部窗口。我们完善了这项技术，以至于我们可以轻松地解决许多与T细胞归巢和胰岛破坏/再生有关的问题。我们还将使用一种新的整体器官成像方法来描绘T1D发育过程中胰腺炎症的整体特征。因此，我们将追求以下具体目标。具体目的1.进一步阐明交叉呈现在T细胞归巢中的作用。具体目标2.研究自然激活的T细胞归巢到胰腺。。 与公共卫生相关：拟议的研究将利用PI实验室开发的新方法来可视化导致自身免疫T细胞破坏产生胰岛素的胰岛的事件。将实时研究T细胞归巢。所获得的知识将有助于开发新的临床胰岛保护和再生策略。

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. . PUBLIC HEALTH RELEVANCE: The proposed research will take advantage of the novel approach developed in the PI's lab to visualize the events leading to destruction of insulin-producing islets by autoimmune T cells. T cell homing will be studied in real-time. The acquired knowledge will be instrumental for development of new clinical strategies for islet protection and regeneration.