Treg Migration in GVHD

GVHD 中的 Treg 迁移

• 批准号: 7890814
• 负责人: Jonathan S. Serody
• 金额: $ 13.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890814
• 关键词: Abbreviations; Address; Affect; Allogenic; Animals; Antigen-Presenting Cells; Behavior Therapy; Biology; CCR5 gene; CCR8 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Clinical; Clinical Trials; Disease; Disease model; Event; Fever; Flow Cytometry; Gastrointestinal tract structure; Genetic Models; Goals; Hematologic Neoplasms; IL2RA gene; Image; Immigration; Immunosuppressive Agents; Inflammatory; Interleukin 2 Receptor; Interleukin-10; L-Selectin; Liver; Lymphoid; Lymphoid Tissue; Mediating; Minor Histocompatibility Antigens; Modeling; Mus; Organ; Pancytopenia; Patients; Pattern; Peripheral; Population; Positioning Attribute; Prevention; Process; Production; Proteins; Role; SELL gene; Secondary to; Severities; Site; Skin; Solid Neoplasm; Spleen; Stem cell transplant; Stimulus; Structure of aggregated lymphoid follicle of small intestine; Syndrome; System; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Tissues; Transplant Recipients; Transplantation; Tumor Necrosis Factor-Beta; Work; base; cell motility; chemokine receptor; cytokine; experience; graft vs host disease; in vivo; knockout animal; lymph nodes; migration; offspring; prevent; protein function; receptor expression; trafficking; tumor

DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is the major limitation to the widespread utilization of allogeneic stem cell transplantation in the treatment of patients with hematological malignancies, solid tumors, bone marrow failure syndromes and congenital diseases. GVHD is mediated by alloreactive donor T cells that recognize major or minor histocompatibility antigens presented by recipient antigen presenting cells. This process leads to a cascade of events that generate proinflammatory cytokines and causes the destruction of recipient cells. The expansion of alloreactive T cells is controlled both by homeostatic proliferation and regulatory T cells. CD4+/CD25+ Treg cells have been shown to be capable of inhibiting GVHD in multiple different murine models and the expansion of these cells for clinical use is feasible. However, little is known about the mechanism of activity of Treg cells in the prevention of GVHD. Whether Treg cells function to suppress alloreactive T cell proliferation in secondary lymphoid tissue or GVHD target organs is not known. The proteins responsible for the migration of Treg cells into secondary lymphoid tissue have not been demonstrated and the affect of blocking the function of the migration of Treg cells is not clear Our group has recently found that the administration of Treg cells that express L-selectin potently inhibited GVHD while Lselectinlo Treg cells had little effect. Additionally, we have recently shown that Treg cells express a different pattern of chemokine receptors after activation, that the chemokine receptor, CCR5, is markedly increased after activation, and that the absence of CCR5 on donor T cells markedly increased the severity of GVHD in irradiated recipient animals. In this proposal, we will investigate the migration of Treg cells in GVHD models. The following three specific aims will be evaluated: Aim 1): To evaluate the function of L-selectin, CCR5 and CCR7 in the migration of Treg cells into secondary lymphoid organs. Aim 2): To evaluate if Treg cells migrate to parenchymal organs in which GVHD occurs in vivo and if this migration is dependent on the expression of chemokine receptors such as CCR4, CCR5 or CCR8. Aim 3): (a) To determine if Treg cell function in GVHD models is dependent on migration to SLT. (b) To determine if the migration of Treg cells is dependent on the presence of Peyer's patches (PP) or the spleen. The overall goals of this work are to provide a better understanding of the mechanism of activity of Treg cells prior to a clinical trial evaluating their effects in blocking GVHD.

描述（由申请人提供）：在血液学恶性肿瘤，实体瘤，骨髓衰竭综合征和先天性疾病的患者治疗中，移植物与宿主疾病（GVHD）是广泛利用同种异体干细胞移植的主要限制。 GVHD是由同种反应性供体T细胞介导的，该细胞识别受体抗原呈递细胞提出的主要或次要的组织相容性抗原。这个过程导致一系列事件产生促炎性细胞因子并导致受体细胞的破坏。 同种异体T细胞的扩展既通过稳态增殖和调节T细胞来控制。 CD4+/CD25+ Treg细胞已被证明能够抑制多种不同的鼠模型中的GVHD，并且这些细胞的扩展供临床使用。然而，关于Treg细胞在预防GVHD中的活性机理知之甚少。 Treg细胞是否功能抑制次级淋巴组织中的同种异体T细胞增殖或GVHD靶器官。尚未证明导致TREG细胞迁移到二次淋巴组织的蛋白质，并且尚不清楚阻止Treg细胞迁移的功能的影响，我们的小组最近发现，在lselectinlo treg细胞的效果很小的同时，pote表达l-链蛋白的Treg细胞均匀地表达了GVHD。此外，我们最近表明，激活后Treg细胞表达了不同的趋化因子受体模式，激活后的趋化因子受体CCR5显着增加，并且供体T细胞上的CCR5不存在CCR5显着增加了受辐射受体中GVHD的严重程度。在此提案中，我们将研究GVHD模型中Treg细胞的迁移。将评估以下三个特定目标： 目标1）：评估L-选择素，CCR5和CCR7在Treg细胞迁移到次级淋巴机构中的功能。 目标2）：评估Treg细胞是否迁移到体内GVHD发生的实质器官，以及这种迁移是否取决于趋化因子受体（例如CCR4，CCR5或CCR8）的表达。 AIM 3）：（a）确定GVHD模型中的Treg细胞功能是否取决于迁移到SLT。 （b）确定Treg细胞的迁移是否取决于Peyer斑块（PP）或脾脏的存在。 这项工作的总体目标是更好地了解Treg细胞活性机理，然后再进行临床试验评估其阻断GVHD的影响。