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 i s 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.
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