The role of the chemokine receptos CCR4 and CCR7 in graft-versus-host disease

趋化因子受体 CCR4 和 CCR7 在移植物抗宿主病中的作用

• 批准号: 7582364
• 负责人: JAMES M COGHILL
• 金额: $ 2.54万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582364
• 关键词: Acute Graft Versus Host Disease; Affect; Allogenic; Animal Model; Animals; Antigen-Presenting Cells; Backcrossings; CC chemokine receptor 4; Cell physiology; Cells; Colon; Effector Cell; Eragrostis; Flow Cytometry; Gastrointestinal tract structure; Goals; Hematopoietic Stem Cell Transplantation; Home environment; Homing; Immigration; Incidence; Inflammation; Knock-out; Knockout Mice; L-Selectin; Laboratories; Lead; Lymphoid Tissue; Mediating; Mesentery; Microscopy; Minor; Morbidity - disease rate; Organ; Pattern; Peripheral; Prevention; Process; Role; Secondary to; Selectins; Site; Skin; T-Lymphocyte; Time; Tissues; Transgenic Organisms; Transplantation; Work; cell motility; chemokine; chemokine receptor; design; graft vs host disease; imprint; improved; in vivo; lymph nodes; migration; mortality; prevent; receptor; trafficking

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). GVHD is mediated by donor T-cells that recognize minor or major MHC disparities in the recipient. Recently, our laboratory and other groups have shown that CD4+CD25+regulatory T cells (Tregs) when infused with allogeneic effector T-cells can block tissue damage and improve survival. The process by which Tregs inhibit effector cell function during GVHD is incompletely understood. The critical site at which this occurs is not clear, the mechanisms by which Tregs migrate into lymphoid tissue is only partly understood, and whether Treg migration to target organs such as the gastrointestinal tract is important in mitigating GVHD has not been explored. The principal goal of this project will be to examine the role of the chemokine receptors CCR4 and CCR7 in the migration of Treg cells during GVHD. To accomplish this, we will use CCR4 and CCR7 knockout mice extensively backcrossed onto a C57BL/6 background. We will isolate CD4+CD25+ Tregs from knockout and wild-type animals, and compare their ability to protect against GVHD when transferred into haplo-identical recipients. In the case of CCR4, we will focus specifically but not exclusively on the role of Treg migration to the skin and gut in preventing complications at these sites and improving overall recipient survival. We will also focus on the hypothesis that CCR7 is required for naive Treg migration into recipient lymph nodes at the time of transplantation, and that this critical step is necessary for previously unstimulated Tregs to protect against GVHD lethality. To evaluate the trafficking of Treg cells we will use flow cytometry and our pioneering work with in-vivo stereofluorescence microscopy using eGFP transgenic wild type, CCR4 -/-, and CCR7-/- animals. The goal of this work is to identify potential targets for the prevention and treatment of GVHD.

描述（申请人提供）：移植物抗宿主病（GVHD）是造血干细胞移植（HSCT）后发病和死亡的主要原因之一。 GVHD 由供体 T 细胞介导，T 细胞可识别受体中轻微或主要的 MHC 差异。最近，我们的实验室和其他团队已经证明，当注入同种异体效应 T 细胞时，CD4+CD25+调节性 T 细胞 (Treg) 可以阻止组织损伤并提高生存率。 Treg 在 GVHD 期间抑制效应细胞功能的过程尚不完全清楚。这种情况发生的关键位点尚不清楚，Treg 迁移到淋巴组织的机制仅部分了解，并且 Treg 迁移到胃肠道等靶器官是否对减轻 GVHD 很重要尚未被探索。该项目的主要目标是检查趋化因子受体 CCR4 和 CCR7 在 GVHD 期间 Treg 细胞迁移中的作用。为了实现这一目标，我们将使用 CCR4 和 CCR7 敲除小鼠广泛回交到 C57BL/6 背景上。我们将从敲除动物和野生型动物中分离出 CD4+CD25+ Tregs，并比较它们在转移至单倍体相同受体时预防 GVHD 的能力。就 CCR4 而言，我们将特别但不仅仅关注 Treg 迁移到皮肤和肠道在预防这些部位的并发症和提高受体总体生存率方面的作用。我们还将重点关注以下假设：移植时幼稚 Treg 迁移到受体淋巴结中需要 CCR7，并且这一关键步骤对于先前未受刺激的 Tregs 来说是必要的，以防止 GVHD 致死。为了评估 Treg 细胞的运输，我们将使用流式细胞术以及我们使用 eGFP 转基因野生型、CCR4 -/- 和 CCR7-/- 动物进行体内立体荧光显微镜的开创性工作。这项工作的目标是确定预防和治疗 GVHD 的潜在目标。