Derived from the plant Cannabis sativa, marijuana is a widely used drug that is primarily known for its psychoactive properties. The primary psychoactive component, delta-9-tetrahydrocannabinol (delta-9-THC), is responsible for its many behavioral and physiological effects which include analgesia as well as changes in memory, cognition, psychomotor skills, mood, perception and immunosuppression. Structure activity relationship (SAR) studies combined with the recent cloning of a G protein-coupled cannabinoid receptor identified in regions of the brain suggests that cannabimimetic agents mediate their CNS effects through specific receptor- ligand interactions. The overall goal of this project is to investigate the mechanisms by which cannabinoid compounds produce immune inhibition by testing the following hypothesis: Immunosuppression by cannabimimetic agents is mediated through a G-protein coupled cannabinoid receptor present on lymphoid cells which when stimulated by cannabimimetic agents produces an intracellular increase in cAMP. The basis for this proposal are five key observations from work in our laboratory supporting the role for a cannabinoid receptor in immunosuppression: (1) [3H]-CP-55,940, demonstrates a high degree of specific binding to lymphoid cells in radioligand binding studies; (2) SAR studies demonstrate that synthetic cannabinoid compounds have a similar rank order of immunoinhibitory potency to that reported with respect to their CNS related effects; (3) cannabinoids demonstrate enantioselective immunosuppression; (4) delta-9- THC and CP-55,940 markedly enhance forskolin-induced intracellular cAMP in lymphoid cells; (5) T-cells are more sensitive to immune inhibition by delta-9-THC than B-cells and macrophages which supports a cAMP-associated mechanism of immunosuppression. Our hypothesis will be tested using the following specific aims: (1) Changes in the phenotypic composition of murine spleen cells isolated from delta-9-THC-treated mice will be characterized by fluorescence activated cell sorting (FACS) analysis; (2) Enantioselective immune inhibition by cannabinoid agents will be further characterized; (3) Cannabinoid receptors on mouse and human lymphoid cells will be verified for the presence of unique regions of mRNA associated with the putative receptor as well as the expression of this receptor using radioligand studies; (4) Modulation of intracellular cAMP through a G protein-coupled mechanism by cannabimimetic agents will be characterized in mouse spleen cells; and (5) the effects of cannabinoids on human lymphoid cell immune function and modulation of cAMP will be investigated.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Sociobehavioral Subcommittee (DAAR)
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Virginia Commonwealth University
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Henriquez, Joseph E; Rizzo, Michael D; Crawford, Robert B et al. (2018) Interferon-?-Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by ?9-Tetrahydrocannabinol. J Pharmacol Exp Ther 367:49-58
Rizzo, Michael D; Crawford, Robert B; Henriquez, Joseph E et al. (2018) HIV-infected cannabis users have lower circulating CD16+ monocytes and IFN-?-inducible protein 10 levels compared with nonusing HIV patients. AIDS 32:419-429
Henriquez, Joseph; Zhou, Jiajun; Li, Jinpeng et al. (2017) Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in immunotoxicology. Toxicol Appl Pharmacol 337:39-44
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Chen, Weimin; Crawford, Robert B; Kaplan, Barbara L F et al. (2015) Modulation of HIVGP120 Antigen-Specific Immune Responses In Vivo by ?9-Tetrahydrocannabinol. J Neuroimmune Pharmacol 10:344-55
Chen, Weimin; Zhang, Quanxuan; Kaplan, Barbara L F et al. (2014) Induced T cell cytokine production is enhanced by engineered nanoparticles. Nanotoxicology 8 Suppl 1:11-23
Karmaus, Peer W F; Wagner, James G; Harkema, Jack R et al. (2013) Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. J Immunotoxicol 10:321-8
Pires, Paulo W; Girgla, Saavia S; McClain, Jonathon L et al. (2013) Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20:650-61
Karmaus, Peer W F; Chen, Weimin; Crawford, Robert et al. (2013) ?9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2. Toxicol Sci 131:419-33
Ngaotepprutaram, Thitirat; Kaplan, Barbara L F; Kaminski, Norbert E (2013) Impaired NFAT and NF?B activation are involved in suppression of CD40 ligand expression by ?(9)-tetrahydrocannabinol in human CD4(+) T cells. Toxicol Appl Pharmacol 273:209-18

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