Notch Signaling in Alloimmunity

同种免疫中的Notch信号传导

• 批准号: 10357913
• 负责人: Ivan Maillard
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-22 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357913
• 关键词: Accounting; Acute; Acute Graft Versus Host Disease; Alloantigen; Allogenic; Anatomy; Antibodies; Antigens; Autoimmunity; B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; Cell Lineage; Cells; Complication; Dangerousness; Data; Development; Disease; Dose; Exposure to; Genetic Transcription; Goals; Homing; Homologous Transplantation; Human; Immune; Immune response; Immune system; Immunity; Immunobiology; Immunologics; Immunosuppression; Individual; Inflammatory; Injury; Intestinal Graft Versus Host Disease; Investigation; Lead; Ligands; Maps; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Onset of illness; Pathogenicity; Patients; Pattern; Positioning Attribute; Production; Regulation; Regulatory T-Lymphocyte; Reporter; Research Project Grants; Role; Signal Transduction; Site; Source; Stromal Cells; T cell response; T-Lymphocyte; Therapeutic; Time; Transgenes; Transgenic Organisms; Transplantation; base; chronic graft versus host disease; cytokine; cytotoxicity; experimental study; graft vs host disease; hematopoietic cell transplantation; immunoregulation; in vivo; insight; isoimmunity; mortality; mouse model; nonhuman primate; notch protein; novel; novel strategies; novel therapeutics; organ transplant rejection; preservation; prevent; programs; radioresistant; receptor; recruit; secondary lymphoid organ; side effect; therapeutic development

ABSTRACT Allogeneic T cell responses against foreign host antigens mediate graft-versus-host disease, the most serious complication of allogeneic hematopoietic cell transplantation (allo-HCT). During the course of this proposal we defined a critical role for Notch signaling in the regulation of pathogenic alloreactive T cells that mediate graft-versus-host disease (GVHD) in multiple mouse models of allo-HCT. Notch inhibition in donor T cells led to long-term protection from GVHD morbidity and mortality. Using monoclonal antibodies, we identified a critical role for Notch1/2 receptors in T cells and Delta-like1/4 (Dll1/4) Notch ligands in the host, with dominant effects of Notch1 and Dll4. Dll1/4 blockade with a short course of antibodies emerged as the most promising strategy to target Notch signaling while avoiding systemic side effects of pan-Notch inhibition. We recently uncovered several remarkable features of Notch regulation in T cell alloimmunity that warrant further investigation. First, we identified specialized radioresistant stromal cells lineage-traced with a Ccl19-Cre transgene as the critical source of Notch ligands in secondary lymphoid organs at the onset of GVHD. These findings uncover a central role for fibroblastic stromal cell subsets in GVHD. Second, short-term inhibition of Delta-like Notch ligands within days after allo-HCT was essential to confer long- term protection from GVHD in multiple mouse models. Within this early time window, Notch induced unique transcriptional effects during the activation of alloantigen-specific T cells that impacted selected aspects of their differentiation. Third, we studied Notch ligand inhibition in a non-human primate allo-HCT model that mimics human transplantation. A single dose of anti-DLL4 antibodies had marked single agent activity to prevent GVHD, showing highly conserved effects of Notch signaling from mice to non-human primates. In both models, we observed an increased ratio of regulatory to conventional T cells in the gut and striking protection from intestinal GVHD, the most dangerous component of acute GVHD. We hypothesize that alloantigen-specific T cells engage in early interactions with specialized subsets of fibroblastic stromal cells expressing Delta-like Notch ligands, inducing a Notch-driven pathogenic and gut-homing program in T cells that promotes GVHD. To explore this hypothesis, we will identify individual subsets of fibroblastic stromal cells that present Dll1 and/or Dll4 Notch ligands to donor-derived T cells early after allo-HCT, map the anatomical sites that support Notch activation in alloreactive T cells, and define the impact of immune- mediate injury on the subsequent integrity of stromal networks in secondary lymphoid organs. In addition, we will identify mechanisms that blunt the accumulation of Notch-deficient T cells in the gut, thus preventing intestinal GVHD, and investigate the early transcriptional effects of Notch signaling in alloreactive T cells. These studies will bring novel insights into the regulation of alloimmunity and might lead to the development of new approaches to limit damaging consequences of T cell reactivity after allogeneic transplantation.

抽象的 针对外来宿主抗原的同种异体 T 细胞反应介导移植物抗宿主病，这是最常见的 异基因造血细胞移植（allo-HCT）的严重并发症。在此期间 我们确定了 Notch 信号在致病性同种反应性 T 细胞调节中的关键作用 在多种同种异体 HCT 小鼠模型中介导移植物抗宿主病 (GVHD)。缺口抑制 供体 T 细胞可长期预防 GVHD 发病率和死亡率。使用单克隆抗体， 我们确定了 T 细胞中的 Notch1/2 受体和 Delta-like1/4 (Dll1/4) Notch 配体在 T 细胞中的关键作用 宿主，Notch1 和 Dll4 具有显着效应。出现了短期抗体阻断 Dll1/4 作为靶向 Notch 信号传导的最有前途的策略，同时避免泛 Notch 的系统副作用 抑制。我们最近发现了 T 细胞同种免疫中 Notch 调节的几个显着特征 值得进一步调查。首先，我们鉴定了专门的抗辐射基质细胞谱系追踪 以 Ccl19-Cre 转基因作为次级淋巴器官中 Notch 配体的关键来源 GVHD 的发生。这些发现揭示了成纤维细胞基质细胞亚群在 GVHD 中的核心作用。第二， allo-HCT 后几天内对 Delta 样 Notch 配体进行短期抑制对于赋予长期 多种小鼠模型免受 GVHD 的长期保护。在这个早期的时间窗口内，Notch 引发了独特的 同种异体抗原特异性 T 细胞激活过程中的转录效应影响了某些方面 他们的差异化。第三，我们在非人灵长类同种异体 HCT 模型中研究了 Notch 配体抑制， 模仿人体移植。单剂抗 DLL4 抗体具有显着的单剂活性 预防 GVHD，显示从小鼠到非人类灵长类动物的 Notch 信号传导高度保守的作用。在 在这两种模型中，我们观察到肠道中调节性 T 细胞与传统 T 细胞的比例有所增加，并且令人震惊 预防肠道 GVHD，这是急性 GVHD 最危险的组成部分。我们假设 同种异体抗原特异性 T 细胞参与与成纤维细胞基质细胞的特殊亚群的早期相互作用 表达 Delta 样 Notch 配体，在 T 细胞中诱导 Notch 驱动的致病性和肠道归巢程序 促进 GVHD。为了探索这一假设，我们将识别成纤维细胞基质的各个亚群 在allo-HCT后早期将Dll1和/或Dll4 Notch配体呈递给供体来源的T细胞的细胞，绘制 支持同种异体反应性 T 细胞中 Notch 激活的解剖位点，并定义免疫影响 介导对次级淋巴器官基质网络随后完整性的损伤。此外， 我们将确定削弱Notch缺陷型T细胞在肠道中积累的机制，从而防止 肠道 GVHD，并研究同种异体反应性 T 细胞中 Notch 信号的早期转录效应。 这些研究将为同种免疫的调节带来新的见解，并可能导致开发 限制同种异体移植后 T 细胞反应性破坏性后果的新方法。