Control of GVHD with Retained GVT

通过保留 GVT 控制 GVHD

• 批准号: 8260364
• 负责人: Robert S Negrin
• 金额: $ 27.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260364
• 关键词: Alloantigen; Allogenic; Animal Model; Animals; Biological; Biology; Bioluminescence; Bone Marrow Transplantation; Cell Transplantation; Cell surface; Cells; Characteristics; Clinic; Clinical Trials; Complex; Development; Dissection; Effector Cell; Ensure; Event; Fluorescence; Functional disorder; Funding; Gastrointestinal tract structure; Gene Expression; Goals; Graft vs Tumor Effect; Hematologic Neoplasms; Hematopoietic; Homologous Transplantation; Human; Image; Immunofluorescence Immunologic; Killer Cells; Label; Life; Light; Liver; Location; Luc Gene; Luciferases; Lymphocyte; Medical; Modeling; Natural Killer Cells; Nodal; Organ; Patients; Population; Proliferating; Proteins; Reaction; Risk; Site; Skin; Source; Structure; T-Lymphocyte; Time; Tissue Sample; Tissues; Transgenic Mice; Translating; Tumor Antigens; base; cancer cell; clinically relevant; clinically significant; cytokine; disorder control; disorder risk; effective therapy; graft vs host disease; image processing; insight; interest; leukemia/lymphoma; migration; novel; older patient; trafficking; tumor

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.

该项目的目标是增强我们对移植物与宿主疾病（GVHD）和 移植物与肿瘤（GVT）反应，以更深入地了解这些复杂的生物学反应并发展 可以转化为诊所的策略。我们将利用一种新颖的生物发光成像策略 因此，感兴趣的细胞种群用荧光素酶（Luc）基因并发出光标记。走向这个 最后，我们生成了独特的GFP/Luc转基因小鼠系，以确保基因表达均匀和 标记的细胞群体的可用性。可以实时遵循Luc*细胞的贩运和存活 高精度和灵敏度。我们将评估主要CD4+和CD* t的GVHD诱导能力 细胞相对于GVHD诱导中关键事件的位置。我们假设GVHD发展 通过淋巴细胞到关键部位的空间和时间迁移，同种反应性细胞增殖 并上调进入GVHD靶器官（例如）所需的其他细胞表面分子 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位点 FACS的GVHD诱导引起的直接组织采样和浸润细胞群体的表征 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 有限的GVHD潜力，可以比较和对比这些细胞的运输和存活特征与 原代T细胞。由于 在临床试验中，两种细胞群体均未导致临床上显着的GVHD，并且可能 促进GVT效应。这个基本和翻译项目将提供有关GVHD病理生理学的见解 并表征能够转化为诊所的GVHD和GVT效应的细胞群体 在项目1中探索CIK单元的地方，该项目与项目1,2,4,5,7和8进行互动 利用所有核心。