Cannabidiol induced apoptosis in T cell to treat autoimmune hepatitis

大麻及其提取物长期以来一直被用来治疗疼痛。然而，它们的精神药效 阻止了它们在医学上的广泛使用。它们的作用被归因于激活了 大麻素受体，CB1和CB2。CB1在细胞质雄性不育系中高度表达，而CB2仅在细胞质雄性不育系中表达 在免疫细胞上表达。我们实验室最近的研究首次证明，自然而然 植物大麻素类化合物大麻二醇(CBD)是一种非精神活性物质，可诱导免疫细胞凋亡。 细胞，在治疗自身免疫性肝炎(AIM)方面非常有效。在目前的研究中，我们还将 验证CBD通过死亡受体和/或诱导T细胞凋亡的中心假设 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手段的机制， 尤其是葡萄球菌肠毒素B(SEB)和刀豆蛋白A诱导的肝炎(CAM)，被认为是 AIM人体实验模型的建立。肝病是发病率和死亡率的主要原因，也是 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，激活的T细胞 淋巴细胞和巨噬细胞似乎在肝脏损伤中起着重要作用。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，我们将研究 以下目标：#1：我们将使用CB1、CB2、CB1/CB2和VR1基因敲除(KO)小鼠来解决 CB1、CB2和香草素受体在CBD诱导T淋巴细胞凋亡信号转导中的作用#2：我们将确定 CBD在体内外诱导免疫细胞凋亡的机制，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Vβ8+T细胞的影响 将对SEB诱导的AIM进行研究。#4：CBD在治疗Con A所致肝炎和肝脏中的应用 伤势将接受测试。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 此外，拟议中的研究将有助于确定其作用机制 通过这种植物来源的非精神活性大麻素，CBD可以有效地治疗 自身免疫性肝炎和肝损伤。

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.