Effects on the Immune System 409immunity. They indicated that THC,∆^8 -THC, 1-methyl∆^8 -THC and abnormal
∆^8 -THC caused immunosuppression, based on reduction of the humoral immune
response to SRBC as measured by spleen plaque-forming cells. Furthermore, this
suppression was not related to CNS activity, since 1-methyl∆^8 -THC and abnormal
∆^8 -THC had minimal CNS activity. Titishov et al. (1989) injected mice with (+) and
(–)enantiomers of the dimethyl heptyl derivative of THC, HU-210 and HU-211,
and reported that they exerted stereospecific effects on the immune system. It was
concluded, however, that immune suppression was effected both by receptor and
non-receptor-mediated modes.
Schatz et al. (1992) reported that inhibition of adenylate cyclase by THC con-
stituted a potential mechanism for cannabinoid-mediated immunosuppression.
Diaz et al. (1993) treated human peripheral blood mononuclear cell cultures with
THC and a variety of cAMP stimulators. Lymphocyte cAMP levels were stimu-
lated using three hormone receptor stimulators, isoproterenol, histamine, orN-
ethylcarboxamide adenosine (NECA), each of which utilizes a different receptor
to enhance cAMP production. THC suppressed cAMP levels independently of the
hormone and receptor utilized. It was suggested that THC exerted its effects on
second messenger systems at the lymphocyte membrane level, and that a pertus-
sis toxin-sensitive Giprotein was involved. Kaminski et al. (1994) also reported
that suppression of the humoral immune response by cannabinoids was medi-
ated partially through inhibition of adenylate cyclase by a pertussis toxin-sensitive
G protein-coupled mechanism. More direct evidence for a role of a cannabinoid
receptor as linked to cannabinoid mediation of immune responses was provided
by Kaminski et al. (1992) when they identified a functionally relevant cannabi-
noid receptor on mouse spleen cells. It was concluded that a cannabinoid receptor
similar, if not identical, to the CB 1 receptor was linked to immune modulation
by cannabimimetic agents. With the cloning of the CB 2 receptor from the human
promyelocytic cell line HL-60 by Munro et al (1993), a more complete picture con-
cerning functional relevance for cannabinoid receptors in the immune system was
obtained. Mckallip et al. (2002) suggested recently that THC-induced apoptosis
in the thymus and spleen of mice, mediated through the CB 2 receptor, serves as
a mechanism for immunosuppression in vitro and in vivo.
Several investigators have addressed the effects of non-psychotropic cannabi-
noids on immune function. Herring et al. (1998) demonstrated that CBN, a ligand
that exhibits higher binding affinity for the CB 2 receptor in comparison to the CB 1
receptor, modulated immune responses and cAMP-mediated signal transduction
in mouse lymphoid cells. The decrease in intracellular cAMP levels resulted in a re-
duction of protein kinase A activity, leading to an inhibition of transcription factor
binding to the cAMP response element andκB motifs. Jan et al. (2002) reported that
CBN enhanced IL-2 expression by T cells that was associated with an increase in
IL-2 distal nuclear factor of activated T cell activity (NF-AT). It was suggested that
this increase was mediated through a CB 1 /CB 2 -independent mechanism. Enhance-
ment of IL-2 also was demonstrated with CP 55,940, THC, and CBD, suggesting
that the phenomenon was not unique to CBN. Luo et al. (1992) examined the effects
of THC,∆^8 -THC, and cocaine on the in vitro mitogen-induced transformation of
lymphocytes of human and mouse origin. The two cannabinoids exerted a biphasic