Do cannabinoids have a therapeutic role in transplantation?

Abstract

Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties. Significant clinical and experimental data on the use of cannabinoids as anti-inflammatory agents exist in many autoimmune disease settings, but virtually no studies have been undertaken on their potential role in transplant rejection. Here we suggest a theoretical role for the use of cannabinoids in preventing allograft rejection. The psychotropic properties of CB1 agonists limit their clinical use, but CB2 agonists may offer a new avenue to selectively target immune cells involved in allograft rejection. Moreover, development of mixed CB1/CB2 agonists that cannot cross the blood-brain barrier may help prevent their undesired psychotropic properties. In addition, manipulation of endocannabinoids in vivo by activating their biosynthesis and inhibiting cellular uptake and metabolism may offer another pathway to regulate immune response during allograft rejection.

Figure 1. Steps of allograft rejection and possible points of interference by cannabinoids

Allograft rejection occurs via three main mechanisms. (a) During direct recognition, donor APC presents donor antigens to recipient’s CD4+ or CD8+ T cells. (b) During indirect recognition, recipient APC activates recipient T cells by presenting donor antigens. (c) Alternatively, recipient APCs can acquire intact donor MHC molecules and undertake direct presentation to recipient T cells. After antigen presentation, T cells are activated and they produce a plethora of cytokines and chemokines leading to the amplification of the immune response. Chemotaxis of different immune cells into the engrafted organ occurs via adhesion and transmigration through the endothelial cells that line the blood vessels. Once in the engrafted tissue, graft cells can be destroyed by direct killing (via the actions of NK and CD8+ cells), by Th1 cells that trigger type-IV hypersensitivity and activate macrophages or via complement activation due to the presence of allo-antibodies. Cannabinoids can interfere with the actions of APCs such as macrophages and dendritic cells, T cells, NK cells and B cells, inhibiting cytokine production and cell proliferation. In addition, cannabinoids can induce apoptosis in activated effector cells such as T cells as well as in antigen presenting cells such as macrophages and dendritic cells, eliminating the cells that are responsible for the amplification of the immune response. Cannabinoids can also interfere with the involvement of endothelial cells in the rejection process by downregulating adhesion molecules and inhibiting transmigration of immune cells into the engrafted tissue. Lastly, cannabinoids can induce Tregs that down-regulate the immune response. Block Induce apoptosis