Cannabidiol induced apoptosis in T cell to treat autoimmune hepatitis

大麻二酚诱导 T 细胞凋亡治疗自身免疫性肝炎

• 批准号: 7394185
• 负责人: Prakash S Nagarkatti
• 金额: $ 33.38万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394185
• 关键词: Acquired Immunodeficiency Syndrome; Acute Hepatitis; Address; Agonist; Alcoholic Hepatitis; Alcoholic Liver Diseases; Analgesics; Apoptosis; Appetite Stimulants; Autoimmune Diseases; Autoimmune Hepatitis; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Caspase Inhibitor; Cell physiology; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Critical Pathways; Cytochromes; Disease; Enterotoxins; Experimental Models; Gene Family; Hepatic; Hepatitis; Human; Immune; Immunosuppression; In Vitro; Inflammatory; Injury; Knock-out; Knockout Mice; Liver; Liver diseases; Lymphocyte Activation; Lymphoid; Mediating; Medicine; Mitochondria; Modality; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Nausea; Organ; Pain; Pathway interactions; Patients; Plants; Play; Principal Investigator; Resistance; Role; Signal Transduction; Splenocyte; Staphylococcal Enterotoxin B; Superantigens; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Viral hepatitis; capsaicin receptor; chronic pain; cytokine; immune function; immunoregulation; in vivo; macrophage; member; mortality; neglect; outcome forecast; prevent; pro-caspase-8; prototype; receptor; response; thymocyte

The plant Cannabis and its extracts have long been used to treat pain. However, their psychotropic effects have prevented their widespread use in medicine. Their effects have been attributed to activation of cannabinoid receptors, CB1 and CB2. CB1 are highly expressed in the CMS, while CB2 is exclusively expressed on immune cells. Recent studies from our lab have demonstrated for the first time that naturally occurring plant cannabinoid, cannabidiol (CBD), which is non-psychoactive, can induce apoptosis in immune cells and is very effective in the treatment of autoimmune hepatitis (AIM). In the current study, we will also test the central hypothesis that CBD induces apoptosis in T cells through death receptor and/or mitochondria! pathways which are responsible for causing immunosuppression. Our studies will address the mechanism by which CBD may serve as a therapeutic modality in the treatment of autoimmune diseases, specifically staphylococcal enterotoxin B (SEB) and ConA-induced hepatitis (CAM), considered to be experimental models for human AIM. Liver disease is a major cause of morbidity and mortality and also the prognosis is poor. In many liver diseases including viral hepatitis, AIM and alcoholic liver disease, activated T lymphocytes and macrophages appear to play an important role in liver damage. AIM is an inflammatory liver disease that is primarily triggered by T cells. To address the effect of CBD on hepatitis, we will pursue the following Aims: # 1: We will use of CB1, CB2, CB1/CB2 and VR1 knockout (KO) mice to address the role of CB1, CB2 and vanilloid receptors in signaling CBD-induced apoptosis in T lymphocytes. # 2: We will identify the mechanisms of CBD-induced apoptosis in immune cells in vitro and in vivo, specifically the role of death receptor pathway versus the mitochondrial pathway. # 3: Effect of CBD on SEB-specific V beta8+ T cells and SEB-induced AIM will be investigated. # 4: Use of CBD in treatment of Con A-induced hepatitis and liver injury will be tested. We will investigate the effects of CBD on T cells, NK cells and NKT cell functions and their ability to produce inflammatory cytokines. Whether the effect of CBD is mediated through cannabinoid or vanniloid receptors will be tested.Together, the proposed studies will help in identifying the mechanisms through which a plant derived non-psychoactive cannabinoid, CBD can be used to effectively treat autoimmune hepatitis and liver injury.

大麻及其提取物长期以来一直被用于治疗疼痛。然而，它们对精神的影响 阻碍了它们在医学上的广泛应用。它们的作用归因于激活了 大麻素受体，CB 1和CB 2。CB 1在CMS中高度表达，而CB 2仅在CMS中表达 在免疫细胞上表达。我们实验室最近的研究首次证明， 大麻二酚（cannabidiol，CBD）是一种非精神活性的植物大麻素，可诱导免疫细胞凋亡， 细胞，并在治疗自身免疫性肝炎（AIM）中非常有效。在本研究中，我们还将 测试CBD通过死亡受体诱导T细胞凋亡和/或 线粒体！导致免疫抑制的途径。我们的研究将解决 CBD可作为治疗自身免疫性疾病的治疗方式的机制， 特别是葡萄球菌肠毒素B（SE B）和ConA诱导的肝炎（CAM），被认为是 人类AIM的实验模型。肝病是发病率和死亡率的主要原因， 预后很差。在包括病毒性肝炎、AIM和酒精性肝病在内的许多肝病中，活化T 淋巴细胞和巨噬细胞似乎在肝损伤中起重要作用。AIM是一种炎症性肝脏 主要由T细胞引发的疾病。为了解决CBD对肝炎的影响，我们将继续研究 以下目的：#1：我们将使用CB 1、CB 2、CB 1/CB 2和VR 1敲除（KO）小鼠来阐明 CB 1、CB 2和香草酸受体在CBD诱导的T淋巴细胞凋亡信号中的作用#2：我们将确定 CBD诱导免疫细胞凋亡的机制在体外和体内，特别是死亡的作用 受体途径与线粒体途径。#3：CBD对SEB特异性V β 8 + T细胞的作用， 将研究SEB诱导的AIM。# 4：CBD在治疗Con A诱导的肝炎和肝脏中的应用 伤害将受到考验。我们将研究CBD对T细胞、NK细胞和NKT细胞功能的影响， 它们产生炎性细胞因子的能力。CBD的作用是否通过大麻素介导 或vanniloid受体将被测试。总之，拟议的研究将有助于确定机制 通过这种方法，一种植物衍生的非精神活性大麻素CBD可以用来有效地治疗 自身免疫性肝炎和肝损伤。