Control of GVHD with Retained GVT

该项目的目标是加强我们对移植物抗宿主病(GVHD)和 移植物抗肿瘤(GVT)反应以更深入地了解这些复杂的生物反应并发展 这些策略可能会转化到临床上。我们将利用一种新的生物发光成像策略 其中感兴趣的细胞群被标记有荧光素酶(Luc)基因并发光。朝向这个方向 最终，我们创造了一个独特的GFP/Luc转基因小鼠系，以确保统一的基因表达和 标记细胞群体的可用性。可以实时跟踪Luc*细胞的贩运和存活 高精度、高灵敏度。我们将评估初级CD4+和CDS*T诱导GVHD的能力 细胞与GVHD诱导中关键事件的位置有关。我们假设GVHD发展成 通过淋巴细胞的空间和时间迁移到关键部位，从而使同种异体反应细胞增殖 并上调进入GVHD靶器官所需的其他细胞表面分子，如 胃肠道、皮肤和肝脏。将利用基于生物发光的成像来识别主要地点 GVHD诱导直接组织取样及FACS对浸润性细胞群的鉴定 和免疫荧光。我们将进一步探索已知具有GVT反应性的细胞群体 比较和对比这些细胞的运输和存活特征的GVHD潜力有限 初级T细胞。我们将重点介绍细胞因子诱导的杀伤(CIK)和自然杀伤(NK)细胞的使用，因为 在临床试验中，这两种细胞群都被证明不会导致临床显著的移植物抗宿主病，并且可能 促进GVT效应。这个基本的和翻译的项目将提供对GVHD病理生理学的见解 并描述了能够产生GVHD和GVT效应的细胞群，这些细胞群可以转化到临床上 在项目1中探索CIK细胞的地方，该项目与项目1、2、4、5、7和8以及 利用所有核心。

The goals of this Project are to enhance our understanding of graft vs host disease (GVHD) and graft vs tumor (GVT) reactions to gain greater insight into these complex biological reactions and to develop strategies which may be translated to the clinic. We will utilize a novel bioluminescent imaging strategy whereby cell populations of interest are labeled with the luciferase (luc) gene and emit light. Towards this end we have generated a unique gfp/luc transgenic mouse line to ensure uniform gene expression and availability of labeled cell populations. Trafficking and survival of luc* cells can be followed in real time with high precision and sensitivity. We will evaluate the GVHD inducing capacity of primary CD4+ and CDS* T cells with respect to the location of key events in GVHD induction. We hypothesize that GVHD develops through the spatial and temporal migration of lymphocytes to key sites whereby alloreactive cells proliferate and upregulate other cell surface molecules required for entry into GVHD target organs such as the gastrointestinal tract, skin and liver. Bioluminescent based imaging will be utilized to identify the major sites of GVHD induction to direct tissue sampling and characterization of the infiltrating cell populations by FACS and immunofluorescence. We will further explore cell populations known to have GVT reactivity yet with limited GVHD potential to compare and contrast the trafficking and survival characteristics of these cells to primary T cells. We will focus on the use of cytokine induced killer (CIK) and natural killer (NK) cells since both cell populations have been shown to not result in clinically significant GVHD in clinical trials and may promote GVT effects. This basic and translational project will provide insights into GVHD pathophysiology and characterize cell populations capable of GVHD and GVT effects that could be translated to the clinic where CIK cells are being explored in Project 1, This Project interacts with Projects 1,2,4,5,7 and 8 and utilizes all of the Cores.