In Vivo Imaging of T-cell Differentiation in Inflammatory Bowel Disease

描述(由申请人提供)：效应器和调节器T细胞在免疫系统的动态平衡中发挥重要作用。最近的研究表明，产生IL-17的效应物，即众所周知的TH-17细胞和Foxp3+调节T细胞，尽管它们的作用明显相反，但它们是从同一来源的幼稚的CD4+T细胞分化而来的。虽然这些细胞在炎症性肠病中的单独作用早已被研究，但对它们在体内炎症条件下的相互分化途径知之甚少。考虑到复杂免疫系统在时间和空间上的动态性质，在小鼠模型上的体内研究非常有吸引力，但由于缺乏非侵入性方法，一直具有挑战性。该项目的第一个具体目标是开发一种新型的高分辨率侧视荧光结肠镜，能够在细胞水平上可视化结肠粘膜。利用这项技术，我们寻求在体内和随着时间的推移，在细胞介导的小鼠结肠炎模型中直接可视化NAOVE CD4+、TH-17和Foxp3+T细胞。该计划的第二个目标是量化结肠炎发展过程中结肠和淋巴器官中相互分化的动力学--每个途径在哪里、何时和在多大程度上被激活。这项研究将为相互分化在炎症性肠病中的作用提供新的见解。尽管目前的重点是T细胞分化，但这里开发的技术和方法将有更广泛的应用，从结直肠癌到许多其他研究，包括炎症相关的肿瘤发生和血管生成，这些都可以受益于微创的活体成像。公共卫生相关性：对胃肠道免疫系统中效应器和调节器T细胞的更好理解可用于开发炎症性肠病的新疗法。细胞水平的侧视结肠镜检查可以提高IBD的临床诊断以及结直肠癌的早期发现。

DESCRIPTION (provided by applicant): Effector and regulator T cells play important roles in the homeostasis of the immune system. Recent studies showed that interleukin-17 producing effectors, known as TH-17 cells, and Foxp3+ regulator T cells, despite their apparently opposite roles, are differentiated from the same origin, naive CD4+ T cells. While the individual roles of these cells in inflammatory bowel disease have long been investigated, little is known about their reciprocal differentiation pathways in the inflammatory conditions in vivo. Considering the dynamic nature -varying in time and space- of complex immune system, in vivo studies in mouse models are highly attractive but have been challenging due to a lack of non-invasive approaches. The first specific aim of this program is to develop a novel high-resolution side-viewing fluorescence colonoscope capable of visualizing the colonic mucosa at the cellular level. Using this technology, we seek direct visualizations of naove CD4+, TH-17, and Foxp3+ T cells in a cell-mediated murine colitis models in vivo and over time. The second aim of the program is to quantify the reciprocal differentiation dynamics -where, when, and to what extent each pathway is activated- in the colon and lymphoid organs in the course of colitis development. This study will provide new insights into the role of the reciprocal differentiation in inflammatory bowel disease. Although the current focus is on T-cell differentiation, the technology and methods developed here will have broader applications ranging from colorectal cancer to numerous other studies, including inflammation-associated tumorgenesis and angiogenesis, that can benefit from minimally-invasive in vivo imaging. PUBLIC HEALTH RELEVANCE: Improved understanding of effector and regulator T cells in the gastrointestinal immune system can be used to develop novel treatment of inflammatory bowel disease. Cellular-level side-viewing colonoscopy may improve the clinical diagnosis of IBD as well as early detection of colorectal cancer.