Effects on the Immune System 3952.3.4
Effects on T Lymphocytes
Studies as early as 1977 indicated that THC alters human T lymphocyte functions
(Nahas et al. 1977). THC has since been reported to suppress a variety of functions
of T cells from a variety of sources, including cytolytic activity and proliferation re-
sponses to T cell mitogens. Klein et al. (1991) examined the effect of cannabinoids
on the activity of murine cytotoxic T lymphocytes (CTLs). The cytolytic activ-
ity of CTLs generated by co-cultivation with either allospecific or trinitrophenol
(TNP)-modified-self stimulators was suppressed by THC and 11-hydroxy-THC.
Allospecific CTLs generated in vivo also were inhibited by in vitro exposure to
these cannabinoids. Drug treatment of mature CTLs appeared to have a minimal
effect on binding of these cells to their targets. In addition, THC inhibited the
proliferation of lymphocytes responding to an allogeneic stimulus as well as the
maturation of these lymphocytes to mature CTLs. Similarly, THC was shown to
inhibit CTL activity developing in vivo. It was proposed that CTL functionality
was inhibited by cannabinoids by at least two modes. First, the cytolytic activity
of mature CTLs was suppressed at a step beyond the binding to the target cell.
Second, cannabinoids appeared to suppress the normal development of mature
effector cells from the less mature precursor state. Fischer-Stenger et al. (1992)
examined the effect of THC on CTL response to herpes simplex virus (HSV)-1
infection. It was indicated that THC decreased CTL activity against virus-infected
cells by inhibiting CTL cytoplasmic polarization toward the virus-infected target
cell. Granule reorientation toward the effector cell-target cell interface following
cell–cell conjugation occurred at a lower frequency in co-cultures containing CTLs
from drug-treated mice. Yerbra et al. (1992) examined effects of THC on one of
the earliest events in T cell activation, the mobilization of cytosolic free calcium
[Ca2+]. It was reported that a portion of the proliferation defect in THC-treated
lymphocytes could be related to a drug induced inhibition of [Ca2+] mobilization
that normally occurs following mitogen treatment.
Schatz et al. (1993) proposed that THC selectively inhibited T cell-dependent
humoral immune responses through direct inhibition of accessory T cell func-
tion. Oral administration of THC to mice produced a selective and dose-related
inhibition of primary humoral immune responses to the T cell-dependent anti-
gen, SRBC, as measured by the AFC response. No inhibitory effect on humoral
responses to the T cell-independent antigen, dinitrophenyl (DNP)-Ficoll was ob-
tained. A similar profile of immune inhibition was observed following direct in
vitro addition of THC to naïve spleen cell cultures sensitized with defined antigens.
In addition, THC produced a marked and dose-related inhibition of anti-CD3 mon-
oclonal antibody-induced T cell proliferation. More recently, Condie et al. (1996)
studied the effects of cannabinoids on adenylate cyclase-mediated signal trans-
duction and IL-2 expression in the murine thymoma-derived T cell line EL4.IL-2.
Treatment of cells with CBN or THC disrupted the adenylate cyclase signaling
cascade by inhibiting forskolin-stimulated cAMP accumulation. This inhibition
led to a decrease in protein kinase A activity and binding of transcription factors
to a cAMP-response element (CRE) consensus sequence. Likewise, an inhibition