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Magnitude Of Stimulation Dictates The Cannabinoid-Mediated Differential T Cell Response To HIVgp120
Chen, W., B. Kaplan, S. Pike, L. Topper, N. Lichorobiec, Steve Simmons, R. Ramabhadran, AND N. Kaminski. Magnitude Of Stimulation Dictates The Cannabinoid-Mediated Differential T Cell Response To HIVgp120. Journal of Leukocyte Biology. Federation of American Societies for Experimental Biology (FASEB), Bethesda, MD, 92(5):1093-102, (2012).
Cannabinoids have immunosuppressive properties, but it is unknown whether cannabinoids further impair the immune status of immunocompromised HIV patients, as approximately 25% of HIV patients smoke marijuana for its putative therapeutic benefit. A surrogate mouse model to induce polyclonal T cell responses against HIVgp120 was established. ∆9-Tetrahydrocannabinol (THC), a plant-derived cannabinoid, suppressed or enhanced mouse CD8+ T cell proliferation and the gp120-specific CTL response when the magnitude of stimulation was high or low, respectively. To determine the molecular mechanisms by which cannabinoids differentially modulate T cell responses, PMA/ionomycin (Io) or anti-CD3/CD28 were used for stimulation, and another plant-derived cannabinoid, cannabidiol (CBD), was investigated. THC or CBD suppressed or enhanced IFN and IL-2 production by mouse splenocytes (SPLC) under optimal or suboptimal stimulation, respectively. Such differential effects of cannabinoids on cytokine production were also observed on nuclear translocation of NFAT and with human PBMC in response to PMA/Io stimulation. However, THC or CBD elevated intracellular calcium, regardless of the stimulation level with PMA/Io, suggesting that the cannabinoid-induced calcium increase provides an appropriate signal for activation in suboptimally stimulated T cells, but an anergic-like signal due to excessive calcium in optimally stimulated T cells. Overall, these data identify a mechanism by which cannabinoids differentially affect T cell function and suggest possible enhancement of immune function by marijuana use among HIV patients.
The chief scientific impact of this study is to elucidate mechanisms by which compounds with well-characterized pharmacological properties such as cannabinoids can improve immune function in immunocompromised patients. The Agency gains by assisting scientific efforts to better understand immune system function and how it is modulated by xenobiotic exposures in susceptible populations.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
GENETIC AND CELLULAR TOXICOLOGY BRANCH