For the past 25 years this grant has investigated health-related consequences associated with marijuana (MJ) smoking and exposure to delta9-tetrahydrocannabinol (THC). We have carried this out with a unique combination of human studies, in vitro experiments, and animal models. In this competing renewal we focus on the role of cannabinoids as immunoregulatory molecules and the mechanisms by which THC suppresses host immunity and increases susceptibility to HIV infection. We have demonstrated that peripheral blood mononuclear cells (PBMC) express cannabinoid receptors and that receptor expression is modulated in MJ smokers, consistent with a direct effect of inhaled THC on circulating immune cells. In modeling the effects of THC on PBMC in vitro, we discovered that THC suppresses human T cell activation and skews cytokine production toward an immunosuppressive profile. Our preliminary studies suggest that both the initiation and maintenance of antigen-specific immunity is impaired by THC. Even more striking, when human PBMC were engrafted into SCID mice, exposure to THC suppressed their capacity to produce IFN-y, enhanced their susceptibility to HIV infection, and dramatically increased systemic viral load. We hypothesize that similar immune modulation occurs in habitual MJ users and may impact their ability to respond to viral infections and vaccines.
Three specific aims are proposed: 1) to define the mechanisms by which THC promotes HIV infection in vivo in the huPBL-NOD/SCID/IL2r-gamma-null model, 2) to investigate the mechanisms by which THC alters the induction and maintenance of antigen-specific immune responses against HIV and Hepatitis B antigens in vitro and in the huPBL-NOD/SCID/IL2r-gamma-null model, and 3) to examine the impact of habitual MJ smoking on humoral and cellular immunity to Hepatitis B (HBV) vaccination under controlled MJ exposure conditions. By the conclusion of this work we will have defined several mechanisms by which THC interacts with and promotes HIV infection. We will also have gained important insight into the impact of THC on the generation of anti-viral immunity and the mechanisms mediating these effects. Our prospective vaccination study will be the first of its kind to directly examine MJ smoking for its impact on a clinically relevant immune response. These findings will help define the interrelationships between MJ abuse and opportunistic infections and provide insight into the appropriate design/use of future HIV and HBV vaccine strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003018-28
Application #
7835552
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Purohit, Vishnudutt
Project Start
1982-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
28
Fiscal Year
2010
Total Cost
$586,689
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Roth, Michael D; Castaneda, Julie T; Kiertscher, Sylvia M (2015) Exposure to ?9-Tetrahydrocannabinol Impairs the Differentiation of Human Monocyte-derived Dendritic Cells and their Capacity for T cell Activation. J Neuroimmune Pharmacol 10:333-43
Castaneda, Julie T; Harui, Airi; Kiertscher, Sylvia M et al. (2013) Differential expression of intracellular and extracellular CB(2) cannabinoid receptor protein by human peripheral blood leukocytes. J Neuroimmune Pharmacol 8:323-32
Harui, Airi; Kiertscher, Sylvia M; Roth, Michael D (2011) Reconstitution of huPBL-NSG mice with donor-matched dendritic cells enables antigen-specific T-cell activation. J Neuroimmune Pharmacol 6:148-57
Sarafian, Theodore; Montes, Cindy; Harui, Airi et al. (2008) Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells. Toxicol Appl Pharmacol 231:282-90
Copersino, Marc L; Boyd, Susan J; Tashkin, Donald P et al. (2006) Quitting among non-treatment-seeking marijuana users: reasons and changes in other substance use. Am J Addict 15:297-302
Copersino, Marc L; Boyd, Susan J; Tashkin, Donald P et al. (2006) Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am J Addict 15:8-14
Hashibe, Mia; Straif, Kurt; Tashkin, Donald P et al. (2005) Epidemiologic review of marijuana use and cancer risk. Alcohol 35:265-75
Boyd, Susan J; Tashkin, Donald P; Huestis, Marilyn A et al. (2005) Strategies for quitting among non-treatment-seeking marijuana smokers. Am J Addict 14:35-42
Yuan, Michael; Kiertscher, Sylvia M; Cheng, Qingwen et al. (2002) Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J Neuroimmunol 133:124-31
Roth, Michael D; Tashkin, Donald P; Choi, Ruth et al. (2002) Cocaine enhances human immunodeficiency virus replication in a model of severe combined immunodeficient mice implanted with human peripheral blood leukocytes. J Infect Dis 185:701-5

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