The role of secondary lymphoid organ fibroblastic cells in alloimmunity

次级淋巴器官成纤维细胞在同种免疫中的作用

• 批准号: 9469208
• 负责人: Eric Thomas Perkey
• 金额: $ 3.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469208
• 关键词: Acute Graft Versus Host Disease; Affect; Alloantigen; Allogeneic Bone Marrow Transplantation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoimmunity; Automobile Driving; Bone Marrow Purging; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinical; Complex; Complication; Data; Disease; Environment; Genes; Genetic; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Neoplasms; Image; Imaging Device; Immune; Immune System Diseases; Immunity; Immunobiology; Immunologics; Immunologist; Infection; Inflammation; Inflammatory; Injury; Investigation; Laboratories; Learning; Life; Ligands; Liver; Lymphoid; MHC Class II Genes; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Physicians; Population; Prophylactic treatment; Regulation; Reporter; Residual Cancers; Role; Scientist; Signal Transduction; Skin; Solid; Source; Spleen; Stromal Cells; Structure; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Training; Transplantation; Up-Regulation; Work; anticancer activity; behavior change; cancer cell; cellular targeting; clinically relevant; conditioning; graft vs host disease; in vivo; intravital imaging; isoimmunity; loss of function; lymph nodes; mortality; mouse model; notch protein; novel; organ transplant rejection; response; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT Allogeneic bone marrow transplantation (allo-BMT) can cure blood cancers and other disorders, but is limited by life-threatening graft-versus-host-disease (GVHD). After myeloablative conditioning and allo-BMT, donor- derived T cells encounter foreign tissue antigens and other critical signals that induce pathogenic alloimmunity and GVHD. To date, our understanding of these signals remains incomplete. We discovered that juxtacrine Notch signals induced by Delta-like1/4 (Dll1/4) ligands are key drivers of lethal GVHD. Alloreactive T cells received Notch signals from non-hematopoietic fibroblastic stromal cells in the spleen and lymph nodes, but not from hematopoietic antigen-presenting cells. Dll1/4 inactivation in Ccl19-Cre+ fibroblastic stromal cells protected recipients from lethal GVHD in a mouse model of myeloablative allo-BMT. However, it is unknown whether fibroblastic stromal cells are essential for GVHD pathogenesis only after myeloablative conditioning and if they can function as a cellular source of alloantigens in addition to presenting Notch ligands. The overall goal of this proposal is to study the role and regulation of fibroblastic stromal cells in T cell immunity, as well as explore their relevance as therapeutic targets in GVHD and other immune disorders. To accomplish this goal, we will investigate two areas of fibroblastic cell immunobiology in two independent Aims. Aim 1 will assess how myeloablative conditioning affects fibroblastic stromal cells as sources of Notch ligands during allo-BMT. We will study how graded intensities of myeloablative conditioning regulate Notch ligand expression and accessibility in subsets of fibroblastic stromal cells and other cell populations that interact with donor T cells. We will determine in real-time if myeloablative conditioning changes the behavior of alloantigen-specific T cells and their early interactions with host fibroblastic and hematopoietic cells. Using clinically relevant mouse allo- BMT models, we will test if fibroblastic cells remain key pathogenic sources of Notch signals driving GVHD even with reduced or no conditioning, which would suggest key functions in broader aspects of immunity. Aim 2 will test if fibroblastic stromal cells function as alloantigen-presenting cells during GVHD. Preliminary evidence suggests that fibroblastic stromal cells upregulate their antigen presentation machinery after allo- BMT. We will investigate the signals that drive this upregulation and use genetic loss of function approaches to test if fibroblastic cell-intrinsic MHC Class II expression contributes to GVHD pathogenesis. In parallel, we will use intravital imaging to study the impact of alloantigens and Notch ligands on early interactions between alloreactive T cells, fibroblastic stromal cells and other antigen-presenting cells at the onset of GVHD. My work has the potential to uncover new functions of fibroblastic stromal cells in GVHD and to suggest a role in broader immunological contexts. In addition, it will provide me with structured learning opportunities in experimental immunobiology that serve my training goals as an immunologist and physician-scientist.

项目摘要/摘要 同种异体骨髓移植（Allo-BMT）可以治愈血液癌和其他疾病，但有限 通过威胁生命的移植物与宿主 - 疾病（GVHD）。在髓质状态调理和供体-BMT之后，供体 - 衍生的T细胞遇到异物抗原和其他诱导致病性同种免疫性的关键信号 和GVHD。迄今为止，我们对这些信号的理解仍然不完整。我们发现近去折叠 Delta Like1/4（DLL1/4）配体引起的Notch信号是致命GVHD的关键驱动因素。同种异体T细胞 从脾和淋巴结中接收到非脊髓性成纤维细胞细胞的缺口信号，但 不是来自造血抗原的细胞。 CCL19-CRE+成纤维细胞细胞中的DLL1/4失活 受保护的接受者免受骨髓性异晶物BMT小鼠模型的致命GVHD。但是，这是未知的 成纤维细胞基质细胞是否仅在骨髓性调节后才至关重要GVHD发病机理 如果它们除了呈现缺口配体外，它们还可以充当同种抗原的细胞来源。总体 该建议的目标是研究成纤维细胞在T细胞免疫中的作用和调节，以及 探索它们作为GVHD和其他免疫疾病中治疗靶标的相关性。为了实现这一目标， 我们将在两个独立目标中研究成纤维细胞免疫生物学的两个领域。 AIM 1将评估如何 骨髓性调节会影响成纤维细胞基质细胞，作为在异子BMT期间的缺口配体的来源。我们 将研究骨髓性调节的分级强度如何调节Notch配体的表达和 与供体T细胞相互作用的成纤维细胞基质细胞和其他细胞群的子集的可及性。 我们将实时确定髓质的调节是否改变了同种抗原特异性T细胞的行为 以及它们与宿主成纤维​​细胞和造血细胞的早期相互作用。使用临床上相关的小鼠allo- BMT模型，我们将测试成纤维细胞是否仍然是驱动GVHD的Notch信号的关键致病源 即使减少或没有调节，这也将暗示免疫的更广泛方面的关键功能。目的 2将测试成纤维母细胞基质细胞在GVHD期间起作用的同种抗原细胞。初步的 有证据表明，成纤维细胞基质细胞在同层后上调其抗原表现机制 BMT。我们将调查驱动此上调的信号，并使用功能方法的遗传丧失 测试成纤维细胞中的MHC II类表达是否有助于GVHD发病机理。同时，我们将 使用插入成像研究同种抗原和缺口配体对早期相互作用的影响 GVHD发作时，同种反应性T细胞，成纤维细胞基质细胞和其他抗原细胞。我的工作 有可能发现GVHD中成纤维细胞基质细胞的新功能，并提出在 更广泛的免疫学环境。此外，它将为我提供结构化的学习机会 实验性免疫生物学，以我作为免疫学家和医师科学家的培训目标。