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The Endocannabinoid System
As an herbal medicine, marijuana has been used for thousands of years for a variety of medical conditions. However, it was not until the 1970s that its effects on the immune system were first noted in terms of inhibition of lymphocyte function and macrophage activity, as measured by the inhibition of macrophage migration inhibitory factor (MIF). Over the next 40 years, it became clear that THC, the psychoactive component of marijuana, exerts its influence on the immune system by activating specialized receptors, Type II cannabinoid receptors (CB2), found on the membranes of every specialized type of cell in the immune system. These receptors are part of a larger class of receptors known as G protein-coupled receptors (GPCRs). They bind substances produced outside the cell. Once the receptor is activated, it relays a signal through an intracellular network, a process known as signal transduction. This process directly affects the expression and activity of other receptors and ultimately results in the translation of the target cells’ genes to produce proteins. These proteins further influence the outer environment in response to the original signal. In the case of the CB2 receptor, it binds a variety of substances produced by the cells themselves -- specialized fatty acids or lipids, known as endocannabinoids -- as well as plant-derived compounds (cannabinoids), for which the system is named. It is currently thought that activation of the CB2 receptors produces a counter-regulatory response to the initial activation of the immune system, an inflammatory response, in order to restore homeostasis. Hence, the cannabinoids are considered anti-inflammatory in nature by facilitating the resolution of inflammation through down-modulation of the immune response, which is accomplished through activation of the CB2 receptors found on every type of immune cell. Receptor Expression However, the expression of these receptors varies according to cell type. The greatest number are found on the antigen-presenting cells (APCs), and the least are found on the T lymphocytes. However, since the APCs typically make the first encounter with a threat, process the antigen and present it to the T lymphocytes, it is now thought that activation of the CB2 receptors on APCs may be more influential on the outcome than activation of the CB2 receptors on the lymphocytes themselves, especially since it has recently been shown that the receptors are not expressed on the T lymphocytes unless they have been activated. Nevertheless, the overall reduction of anti-inflammatory proteins by APCs in concert with the lymphocytes is ultimately beneficial to the host.HIV Disease In the context of HIV disease, recently published research showed that CB2 ligands could inhibit the migration of macrophages towards the trans-activating (tat) protein of HIV and concluded: “…the immunosuppressive and anti-inflammatory properties of select cannabinoids may have profound therapeutic potential in moderating HIV-associated immunopathology, including microglial activation, chemokine/cytokine dysregulation, and monocyte infiltration in the CNS.”Immugen will continue to support research in this area and seek an early indication for the prevention and treatment of AIDS-related dementia. Additionally, the inhibition of immune cell migration and function has a potential application as a topical agent to prevent the transmission of the virus at the site of entry either vaginally or rectally.
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