Cannabinoid-mediated mitigation of graft versus host disease: Roles of CB2 receptors and adenosine signaling

大麻素介导的移植物抗宿主病缓解：CB2 受体和腺苷信号传导的作用

• 批准号: 9402352
• 负责人: William R. Drobyski
• 金额: $ 53.87万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402352
• 关键词: 2-arachidonylglycerol; ADORA2A gene; Acute; Acute Graft Versus Host Disease; Address; Adenosine; Agonist; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Biology; Bone Marrow Transplantation; CNR2 gene; Calcineurin; Cannabidiol; Cannabinoids; Cannabis; Cells; Chronic Phase; Chronic Phase of Disease; Clinical; Complication; Development; Disease; FOXP3 gene; Fibrosis; Fostering; Functional disorder; Gastrointestinal tract structure; Genetic; Goals; Hematopoietic; Hematopoietic Stem Cell Transplantation; Immune; Inflammation; Inflammatory; Lead; Ligands; Liver; Mediating; Morbidity - disease rate; Organ; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phase; Play; Population; Production; Purinergic P1 Receptors; Receptor Signaling; Regulatory T-Lymphocyte; Reporter; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Site; Skin; Stem cell transplant; Syndrome; Testing; Time; Transplant Recipients; base; chronic graft versus host disease; clinically relevant; cytokine; design; experimental study; graft vs host disease; insight; mortality; mouse model; novel; novel strategies; phytocannabinoid; preclinical study; prevent; receptor; receptor expression; reconstitution; stem; treatment strategy

Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation, and is characterized by both acute and chronic phases which have different pathophysiological mechanisms. Despite the use of pharmacological strategies which are primarily based on the administration of calcineurin-based agents, both acute and chronic GVHD remain major clinical problems. In preliminary studies, we have identified that signaling through the cannabinoid type 2 receptor (CB2R) mitigates the severity of both acute GVHD and also plays a pivotal role in reducing fibrosis in chronic GVHD. Moreover, we have discovered that that the nonpsychoactive, phytocannabinoid, cannabidiol (CBD) also inhibits GVH reactivity and potentiates adenosine signaling. Based on these studies, our overall hypothesis is that cannabinoids mitigate the severity of both acute and chronic GVHD, and that these anti-inflammatory effects are mechanistically mediated through the CB2R and the adenosine receptor signaling pathways. Studies in Specific Aim 1 will utilize a novel CB2R reporter mouse model that has flanking lox P sites that will allow us to both identify the critical immune cell populations that express the CB2R, and then eliminate these identified cells to formally test a functional role for these cells in acute GVHD biology. We will also employ several clinically relevant pharmacological approaches to determine whether administration of direct and selective CB2R agonists or, alternatively agents that inhibit the degradation of 2-arachidonyl glycerol (2-AG) which is the major endogenous ligand for the CB2R, can reduce the severity of this disease. Studies in Specific Aim 2 will define the role of CBD in mitigating the severity of acute GVHD by using selective pharmacological antagonists and genetic strategies to test the hypothesis that CBD regulates GVHD through the adenosine 2A receptor (A2AR) signaling pathway. We will also examine whether CBD augments the reconstitution of regulatory T cells and stabilizes Foxp3 expression in these cells through adenosine signaling. Experiments in Specific Aim 3 will determine whether cannabinoid signaling prevents the development of chronic GVHD-associated fibrosis which is a hallmark of this disease. Specifically, we will define the critical CB2R expressing immune cell populations which are present during the fibrotic phase of chronic GVHD and use cell-specific Cre-lox deletion approaches to define the functional significance of CB2R expression in identified cells. We will also assess whether either pharmacological administration of direct CB2R agonists, agents that inhibit the degradation of 2-AG, and CBD can prevent chronic GVHD-associated fibrosis. The overall goal of these studies is to define the mechanisms by which cannabinoids modulate both acute and chronic GVHD, and to test clinically relevant strategies that are designed to mitigate these complications in allogeneic hematopoietic stem cell transplant recipients.

移植物抗宿主病（GVHD）是异基因造血干细胞移植的主要并发症 细胞移植，其特征在于具有不同的急性和慢性阶段， 病理生理机制尽管使用的药理学策略主要是基于 基于钙调神经磷酸酶的药物给药，急性和慢性GVHD仍然是主要的临床 问题在初步研究中，我们已经确定了通过大麻素2型的信号传导， 受体（CB 2 R）可减轻急性GVHD的严重程度，并在减少纤维化方面发挥关键作用 慢性移植物抗宿主病此外，我们发现，非精神活性的植物大麻素， 大麻二酚（CBD）还抑制GVH反应性并增强腺苷信号传导。基于这些 研究，我们的总体假设是大麻素减轻了急性和 慢性GVHD，并且这些抗炎作用是机械介导的 通过CB 2 R和腺苷受体信号通路。研究具体目标1 将利用一种新的CB 2 R报告小鼠模型，该模型具有侧翼lox P位点，这将使我们能够 鉴定表达CB 2 R的关键免疫细胞群，然后消除这些鉴定的免疫细胞群。 细胞，以正式测试这些细胞在急性GVHD生物学中的功能作用。我们还将雇用几名 临床相关的药理学方法，以确定是否给予直接和选择性 CB 2 R激动剂或抑制2-花生四烯酸甘油（2-AG）降解的试剂， 是CB 2 R的主要内源性配体，可减轻该病的严重程度。具体研究 目标2将通过使用选择性的抗GVHD药物来定义CBD在减轻急性GVHD严重程度中的作用。 药理学拮抗剂和遗传学策略来检验CBD调节GVHD的假设 腺苷2A受体（A2 AR）信号通路。我们还将研究CBD是否 增强调节性T细胞的重建，并通过以下途径稳定这些细胞中Foxp 3的表达： 腺苷信号具体目标3中的实验将确定大麻素信号传导是否 防止慢性GVHD相关纤维化的发展，这是这种疾病的标志。 具体地，我们将定义在免疫过程中存在的关键CB 2 R表达免疫细胞群体。 慢性GVHD的纤维化阶段，并使用细胞特异性Cre-lox缺失方法来定义 在鉴定的细胞中CB 2 R表达的功能意义。我们还将评估 直接CB 2 R激动剂、抑制2-AG降解的药剂的药理学施用，以及 CBD可以预防慢性GVHD相关的纤维化。这些研究的总体目标是确定 大麻素调节急性和慢性GVHD的机制，并测试临床相关性 旨在减轻同种异体造血干细胞移植中这些并发症的策略 移植接受者