Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo

Abstract

Killer lymphocytes play a major role in host defense against tumors and infectious diseases. Previously, we reported that delta-9-tetrahydrocannabinol (THC) and II-hydroxy-delta-9-tetrahydrocannabinol (II-hydroxy-THC) suppressed the cytolytic activity of cultured natural killer (NK) cells. Also, we showed that the drugs appeared to be affecting a stage in the killing process subsequent to the binding of the killer cell to the target cell. In the present report, we have extended these studies to an examination of the effect of cannabinoids on the activity of cytotoxic T lymphocytes (CTLs). The cytolytic activity of CTLs generated by cocultivation with either allospecific stimulators or TNP-modified-self stimulators were suppressed by both THC and II-hydroxy-THC treatment. Allospecific CTLs generated in vivo were also inhibited by an in vitro exposure to either THC or II-hydroxy-THC, and the sensitivity of these cells to drug effects appeared to be greater than the sensitivity of the in vitro generated CTLs. Suppression of cytolytic function by THC and II-hydroxy-THC was maximal after a 4-h drug treatment, suggesting that the drug effects were inducible and therefore required a finite period of time to develop maximally. As seen in previous studies involving NK cells, drug treatment of mature CTLs appears to have little effect on the binding capacity of these cells for the target. However, the maximal killing capacity of the cells and the frequency of CTLs were significantly reduced by drug treatment. In addition to suppressing the cytolytic activity of mature effector CTLs, we also show that drug treatment inhibits both the proliferation of lymphocytes responding to an allogeneic stimulus and the maturation of these lymphocytes to mature CTLs. Similarly, CTL activity developing in vivo could be inhibited by THC injection. These results suggest that CTLs are inhibited by cannabinoids by at least two mechanisms. First, the cytolytic activity of mature killers is suppressed at some point beyond the binding to the target cell. Second, the cannabinoids appear to suppress the normal development of these mature effector cells from less mature precursor cells.

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes

“…While the immunosuppressive effects of cannabinoids (Cabral and Vasquez, 1992;Morahan et al, 1979) and their modulatory activities on immune cell functions (Cabral and Mishkin, 1989;Fischer-Stenger et al, 1992;Klein et al, 1991) have been reported previously, there is recent evidence supporting the premise that cannabinoids also have anti-inflammatory (Pryce et al, 2003), neuroprotective (Shen and Thayer, 1998), and anti-tumor properties (GalveRoperh et al, 2000). Cannabinoids have been shown to be neuroprotective in a variety of in vitro and in vivo models of neuronal excitotoxicity (van der Stelt and Di Marzo, 2005;McCarty, 2006).…”

The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

“…6). A nonexhaustive list of in vitro effects includes inhibition of the proliferative responses of T lymphocytes (7), inhibition of cytotoxic T cell activity (8), suppression of macrophage function and antigen presentation (9,10), and inhibition of NO production by macrophages (11). Reports on the in vitro effects of CBD on immune cells are scarce and include the modulation of tumor necrosis factor (TNF), IL-1, and IFN-␥ by human peripheral blood mononuclear cells (12,13) and the suppression of chemokine production by a human B cell line (14).…”

Cannabinoid‐receptor expression in human leukocytes

“…However, a variety of suppressive and inhibitory effects on the immune response induced by A-9-tetrahydrocannabinol (A9-THC), which is the major psychoactive component of marijuana, has been described both in vivo and in vitro (Baczynsky and Zimmerman, 1983;Titishov et al, 1989). The immunosuppressive effects of d9-THC include the inhibition of mitogen-induced T lymphocyte proliferation (Pross et al, 1987;Luo et al, 1992), the inhibition of y-interferon production (Blanchard et al, 1986) and the suppression of induction and cytolytic function of cytotoxic T cells (Klein et al, 1991). As A9-THC has proved unsatisfactory as a probe for the cannabinoid receptor due to non-specific binding to everything including cell membranes (Marx, 1990), the possibility that A9-THC might yield its effects simply by perturbing cell membranes and thereby altering cellular functions has been raised (Tahir and Zimmerman, 1991 ;Watzl et al, 1991).…”