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- [Delta]2079-tetrahydrocannabinol-mediated suppression of the Interferon-alpha (IFNalpha) response by plasmacytoid dendritic cells and IFNalpha-mediated activation of T cells in healthy and human immunodeficiency virus (HIV) infected human subjects
- Henriquez, Joseph Edgar
- Electronic Theses & Dissertations
Δ9-tetrahydrocannabinol (THC) is the primary psychoactive cannabinoid congener in Cannabis sativa and is a well characterized modulator of immune activation. In murine models, treatment with THC can exacerbate viral and bacterial infection, in part, by suppression of the inflammatory cytokine response. One of the key classes of cytokines suppressed by THC is type I interferons (IFN), a group of cytokines consisting of IFNα and IFNβ. The primary source of IFNα during acute antiviral immune...
Show moreΔ9-tetrahydrocannabinol (THC) is the primary psychoactive cannabinoid congener in Cannabis sativa and is a well characterized modulator of immune activation. In murine models, treatment with THC can exacerbate viral and bacterial infection, in part, by suppression of the inflammatory cytokine response. One of the key classes of cytokines suppressed by THC is type I interferons (IFN), a group of cytokines consisting of IFNα and IFNβ. The primary source of IFNα during acute antiviral immune responses is the Plasmacytoid Dendritic Cell (pDC), which can secrete 1000-fold more IFNα than other circulating peripheral blood mononuclear cells (PBMC). Paradoxically, patients infected with human immunodeficiency virus (HIV), a chronic viral infection that causes immunodeficiency via infection and depletion of CD4+ T cells, have fewer circulating pDC with a reduced capacity to secrete IFNα. Furthermore, circulating pDC number has been correlated with CD4+ T cell number and treatment with IFNα can reduce HIV-mediated CD4+ T cell depletion. Conversely, hyperactivation of pDC is associated with T cell exhaustion and is implicated in HIV-associated neurocognitive disorders (HAND). Interestingly, many HIV patients utilize medicinal cannabinoids to combat the effects of chronic HIV infection. The focus of this project was to determine if IFNα-mediated stimulation of T-cells can be suppressed by THC by testing the following hypothesis: THC will suppress TLR-9-dependent activation of pDC, subsequent efficacy of pDC-mediated T cell activation, and CD8+ T cell-mediated activation of astrocytes. These studies revealed that CpG-ODN-induced IFNα secretion and expression of CD83, a costimulatory molecule, by pDC is suppressed by THC in a concentration dependent manner. Furthermore, key intracellular signaling events required for inflammatory cytokine secretion by pDC were suppressed by treatment with THC and CBR2-specific agonists in pDC from healthy donors. Additionally, pDC from HIV+ donors were more sensitive to THC-mediated suppression than pDC from healthy donors. Treatment with THC also inhibited IFNα-mediated activation of CD4+ and CD8+ T cells from healthy and HIV+ donors. Specifically, treatment with THC diminished IFNα-induced IL-7R expression, cognate signaling, and subsequent proliferation. Interestingly, and in contrast to the results in pDC, T cells from HIV+ donors were less sensitive to the suppressive effects of THC. Finally, stimulation by CD3/CD28/IFNα induced the secretion of IFNγ and TNFα by CD8+ T cells from healthy donors. Further, IFNγ and TNFα induced secretion of inflammatory cytokines by U251 astrocytes. Coculture of CD8+ T cells with U251 astrocytes and direct stimulation of U251 astrocytes with recombinant TNFα and IFNγ revealed that treatment with THC reduced both the activation and secretion of cytokines from CD8+ T cells and the subsequent cytokine-mediated stimulation of the U251 astrocytes. Collectively, these studies have provided evidence for the use of cannabinoids in ablating the type of neuroimmune interactions which can lead to HAND by demonstrating that THC can suppress the activation of pDC, and subsequent activation of T cells and astrocytes.