title: Δ⁹-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells.
abstract: Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2(k) splenocytes into H-2(b) mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection-indicator cytokines, including IL-2 and IFN-γ. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection.
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Sido
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA.
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA mitzi.nagarkatti@uscmed.sc.edu.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006087:Graft vs Host Reaction / Q000187:drug effects / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D016038:Skin Transplantation; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol
keywords: T cell suppression; THC; allograft tolerance; skin allograft