Effects on the Immune System 401nity as demonstrated by reduced production of IFN-γand antibodies to IgG2a.
BALB/c mice, infected with a primary sublethal dose ofL. pneumophila de-
veloped resistance to a larger challenge infection. Intravenous injection of THC
1 day prior to primary infection resulted in increased mortalities after a chal-
lenge infection. Furthermore, the level of anti-L. pneumophilaIgG 1 antibodies in
THC-treated animals, which are stimulated by Th 2 cells, was elevated. In con-
trast, levels of Th 1 -regulated, IgG2awere depressed. The investigators suggested
that THC decreases the development of anti-L. pneumophilaimmunity by caus-
ing a change in the balance of Th 1 and Th 2 functional activities. In a follow-up
study, Klein et al. (1997) examined the effects of CBD and CBN, as well as CP
55,940, on sublethal infection of inbred BALB/c mice that are relatively resistant
to infection withL. pneumophila. CBD and CBN did not affect mortality of mice
sublethally infected withLegionellato as great an extent as THC. However, CP
55,940 yielded levels of mortalities that were comparable to those induced by
THC consistent with augmented lethality. Furthermore, mice receiving THC be-
fore and after infection exhibited higher levels of bacteria in their lung compared
to sublethally infected mice not receiving cannabinoid. In addition, lung levels
of mRNA for IL-6 were increased markedly following treatment of infected ani-
mals with THC. More recently, Klein et al. (2000) reported that THC treatment
of BALB/c mice results in suppression of not only IFN-γbut also IL-12 and IL-
12 receptorβ2inresponsetoL. pneumophilainfection. Studies using receptor
antagonists suggested that both the CB 1 and CB 2 receptors were linked function-
ally to the suppression of Th 1 immunity toLegionella,resulting in a decrease
in IFN-γand IL-12. In addition, Cabral and Marciano-Cabral (2004) noted that
cannabinoid-mediated exacerbation of brain infection withAcanthamoeba in-
volved alterations in levels of cytokines. It was shown that mice administered
THC and infected withAcanthamoebaexhibited dose-related higher mortalities
than infected vehicle controls. The greater severity of disease for THC-treated
mice was accompanied by decreased accumulation of macrophage-like cells at
focal sites of infection in the brain. Furthermore, THC resulted in decreased lev-
els of mRNA for the pro-inflammatory cytokines IL1-α, IL1-β, and TNF-αfor
neonatal rat microglia co-cultured withAcanthamoeba, implicating these resident
macrophages of the brain as targets of cannabinoid-mediated decreased resis-
tance.
The studies that have been performed on experimental animals have utilized
THC doses in the range of 0.2 to 100 mg/kg. These doses have been administered
by different routes to guinea pigs and mice or other rodents. The concentrations
of THC measured in the circulation of these animals are achievable in human
marijuana smokers following appropriate extrapolation for mass/surface ratio
(Rachelefsky and Opelz 1977).