Impact of THC on Human Immune Responses and TCell Activation

In addition to animal models, there are several epidemiological studies suggesting that marijuana smoking can predispose to the development of opportunistic infections and cancer. Tindall et al. (83) collected careful drug use histories from 386 HIV-positive individuals and observed a significantly more rapid progression from HIV infection to AIDS in those who smoked marijuana. Similarly, Newell and associates (84) found marijuana use to be associated with the acquisition of opportunistic infections and/or Kaposi's sarcoma in patients with HIV (OR 3.7). Caiaffa et al. (85) also observed that the smoking of illicit drugs, including marijuana and/or cocaine, was statistically associated with the development of bacterial pneumonia in HIV-positive individuals (OR 2.24). More recently, marijuana use was identified in one large study as an independent risk factor for the development of head and neck cancer (51).

To evaluate the impact of THC on human immune responses, Yuan et al. (86) purified T-cells from the blood of healthy volunteers and stimulated them ex vivo with antigen-presenting cells in the presence or absence of THC. THC inhibited T-cell proliferation in a dose-dependent manner, with 5 ^g/mL inhibiting activation by an average of 53% (range 28-79%) compared with control cells. Hypothesizing that this effect was associated with a change in the balance of Th1 and Th2 cytokines, superna-tants were harvested from the T-cell cultures and examined for the presence of IFN-y and IL-4. IFN-y concentrations were reduced on average by 50%, whereas IL-4 levels were increased on average to 110%, resulting in a significant shift in Th1/Th2 cytokine

Fig. 4. Tetrahydrocannabinol (THC) shifts the capacity for activated T-cells to produce T-helper type 1 (Th1) and T-helper type 2I (Th2) cytokines. Purified human T-cells were activated with a combination of monoclonal antibodies directed against the T-cell receptor (CD3) and costimulatory molecules (CD28) in the presence of control medium (left panel) or medium supplemented with interleukin (IL)-12 (10 ng/mL, middle panel) or THC (5 Mg/mL, right panel). Cells were permeabilized, and the production of interferon (IFN)-y, a Th1 cytokine, and IL-4, a Th2 cytokine, was detected in each cell by flow cytometry. IL-12 increased the Th1/Th2 ratio, whereas THC decreased the production of IFN-y and the Th1/Th2 ratio.

Fig. 4. Tetrahydrocannabinol (THC) shifts the capacity for activated T-cells to produce T-helper type 1 (Th1) and T-helper type 2I (Th2) cytokines. Purified human T-cells were activated with a combination of monoclonal antibodies directed against the T-cell receptor (CD3) and costimulatory molecules (CD28) in the presence of control medium (left panel) or medium supplemented with interleukin (IL)-12 (10 ng/mL, middle panel) or THC (5 Mg/mL, right panel). Cells were permeabilized, and the production of interferon (IFN)-y, a Th1 cytokine, and IL-4, a Th2 cytokine, was detected in each cell by flow cytometry. IL-12 increased the Th1/Th2 ratio, whereas THC decreased the production of IFN-y and the Th1/Th2 ratio.

balance similar to that observed in animal models (44,74,75). When examined at the single cell level, THC decreased both the number of T-cells producing IFN-y and the average cytokine production per cell (Fig. 4). CD4+ and CD8+ T-cells were both equally suppressed. The impact of THC on the subsets was also examined at the level of mRNA expression using a ribonuclease protection assay to simultaneously assay for both Th1 (IL-2, IFN-y) and Th2 (IL-4, IL-5) cytokines. Consistent with the results obtained by enzyme-linked immunosorbent assay and single cell analyses, mRNA encoding for IFN-y and IL-2 was reduced by 21-48% in cells treated with 5 Mg/mL THC, and mRNA encoding for IL-4 and IL-5 was increased by 1.5- to 11.2-fold. Pretreatment with SR144528, a CB2-selective antagonist, prevented the majority of the THC-mediated effects, whereas there was little response to AM251, a selective CB1 antagonist. This work suggests a strong correlation between murine models and human studies, with THC acting via cannabinoid receptors to suppress antigen-specific T-cell activation and skew responding T-cells toward a Th2 profile (86).

As in the mouse model by Zhu et al. (44), THC also upregulates the production of TGF-P when human T-cells are activated by immobilized anti-CD3 (68). TGF-P, although not a classic Th2 cytokine, inhibits T-cell proliferation, suppresses production of IL-2 and IFN-y, and antagonizes the activation of both lymphocytes and monocytes. As little as 50 ng/mL of THC increased the production of TGF-P two- to threefold, and 5 Mg/mL of THC increased the release of TGF-P protein fivefold. To evaluate the role of cannabinoid receptors in this response, human T-cells were pretreated with either pertussis toxin, forskolin, or methylxanthine before activation in the presence of THC. Inactivation of G protein-coupled receptors by pertussis toxin, activation of adenyl cyclase by forskolin, and inactivation of phosphodiesterase activity by methylxanthine all blocked the capacity for THC to induce TGF-P consistent with signaling via cannabinoid receptors. Selective CB1 or CB2 receptor antagonists were then used to confirm that signaling was mediated via the CB2 receptor. It is entirely possible that upregulation of TGF-P by THC mediates many of its immunological consequences on human cells, as it does on mouse cells, but experiments to test this hypothesis have not yet been carried out.

Continue reading here: Immunological Suppression of Alveolar Macrophages in the Lungs of Habitual Marijuana Smokers

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