In Vivo Properties of Ex vivo Expanded CD25+ T Cells

离体扩增 CD25 T 细胞的体内特性

• 批准号: 7227028
• 负责人: VU H NGUYEN
• 金额: $ 12.73万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-02-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227028
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Affect; Alloantigen; Animal Model; Antigen-Presenting Cells; Autoimmune Diseases; Bioluminescence; Bone Marrow Transplantation; Cell Differentiation process; Cell Transplantation; Cells; Clinical; Cytomegalovirus; Data; Disease; Disruption; Exposure to; Flow Cytometry; Goals; Graft vs Tumor Effect; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic; Home environment; Homeostasis; Homing; IL2RA gene; Image; Immune; Immune response; Immunoglobulin Variable Region; Immunology; Immunotherapy; Infection; Infusion procedures; Knock-out; Knockout Mice; L-Selectin; Label; Laboratories; Lead; Luciferases; Lymphoid; Modeling; Mus; Natural regeneration; Non-Malignant; Organ; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Proliferating; Property; Range; Research; Research Personnel; Role; Secondary to; Site; Solid Neoplasm; T-Lymphocyte; Techniques; Testing; Training Programs; Transgenic Mice; Translations; Transplant Recipients; Transplantation; Work; graft vs host disease; human study; immunoregulation; in vivo; innovation; insight; integrin beta7; interest; migration; pre-clinical; progenitor; reconstitution; skills; trafficking; tumor

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation is potentially curative for a variety of hematologic cancers. However, graft vs host disease (GVHD) and the lack of donors limit their wide application. CD4+CD25+ regulatory T cells (Treg) can suppress aberrant immune responses and regulate peripheral T cell homeostasis. We recently show that Treg suppress GVHD without abrogating the graft vs tumor effect in a murine model. However, their rarity and our lack of understanding of their immunoregulation limit their use in the clinical setting. This proposal details a 5-year training program. The long-range goal of this project is to determine whether ex vivo expanded Treg add benefit to HCT. The objective of this project is to evaluate the role of ex vivo expanded Treg in animal models of HCT. The central hypothesis to this work is that Treg can be expanded ex vivo and that such population provide benefits in the post-HCT period. This hypothesis will be tested by pursuing three specific aims: 1) evaluate the in vivo survival and trafficking of ex vivo expanded Treg using ICFSE labeling, flow cytometry, and bioluminescence imaging of Treg from luciferase transgenic mice; 2) evaluate the effects of altered Treg homing and migration on GVHD and the graft vs tumor (GVT) using knockouts of L-selectin and alpha4-beta7 integrin; 3) determine how ex vivo expanded Treg alter the immune reconstitution of the donor graft with spectratype analysis, phenotyping of lymphoid organ and peripheral blood mononuclear cells via flow cytometry, and functional analysis by CMV infection. The proposed work is innovative because we study a rare population of cells using noninvasive techniques in sensitive animal models of GVHD and GVT. It is expected that our studies will provide preclinical information that is important for human studies. The proposed training program is in a supportive and dynamic research setting. Thus, the candidate will gain the necessary skills to become a successful independent investigator in the field of transplant immunology.

描述（由申请人提供）： 造血细胞移植对多种血液系统癌症有潜在的治疗作用。然而，移植物抗宿主病（GVHD）和缺乏供体限制了其广泛应用。CD 4 + CD 25+调节性T细胞（Treg）可以抑制异常的免疫应答并调节外周血T细胞的稳态。我们最近在小鼠模型中显示Treg抑制GVHD而不消除移植物抗肿瘤效应。然而，它们的稀有性和我们对其免疫调节的缺乏了解限制了它们在临床环境中的使用。这份提案详细说明了一项为期5年的培训计划。该项目的长期目标是确定离体扩增的Treg是否增加HCT的益处。本项目的目的是评估体外扩增的Treg在HCT动物模型中的作用。这项工作的中心假设是Treg可以离体扩增，并且这样的群体在HCT后时期提供益处。该假设将通过追求三个具体目标来测试：1）使用来自荧光素酶转基因小鼠的Treg的ICFSE标记、流式细胞术和生物发光成像来评估离体扩增的Treg的体内存活和运输; 2）使用L-选择素和α 4-β 7整联蛋白的敲除来评估改变的Treg归巢和迁移对GVHD和移植物抗肿瘤（GVT）的影响; 3）通过谱型分析、通过流式细胞术对淋巴器官和外周血单核细胞进行表型分析以及通过CMV感染进行功能分析来确定离体扩增的Treg如何改变供体移植物的免疫重建。这项工作是创新的，因为我们在敏感的GVHD和GVT动物模型中使用非侵入性技术研究了一种罕见的细胞群体。预计我们的研究将提供对人体研究重要的临床前信息。拟议的培训计划是在一个支持和动态的研究环境。因此，候选人将获得必要的技能，成为移植免疫学领域成功的独立调查员。