388 G.A. Cabral and A. Staab
a cannabinoid receptor identical to, or that shared homology with that in brain,
was present in cells of the immune system. In 1993, Munro and colleagues (Munro
et al. 1993) reported on the molecular characterization of a peripheral cannabinoid
receptor from a human promyelocytic leukemia cell line HL-60 that was distinctive
from the CB 1 receptor. The cloned receptor was not expressed in the brain but was
localized in macrophages in the marginal zone of the spleen. Subsequent studies
have confirmed and extended these observations and have indicated that gene
products for this receptor, designated CB 2 , are localized primarily in cells of the
immune system, including B lymphocytes, macrophages and monocytes, natural
killer (NK) cells, and T lymphocytes (Galiègue et al. 1995; Bouaboula et al. 1993).
The CB 2 receptor also is expressed in vitro by microglia (Carlisle et al. 2002; Sinha
et al. 1998), a population of resident macrophages of the brain and eye.
Since the discovery of the CB 1 and CB 2 receptors, major advances in cannabi-
noid pharmacology and physiology have been made and novel insights into the
functional role of cannabinoids and their cognate receptors in the immune system
have been obtained. The discovery of receptors for exogenous cannabinoids im-
plied the existence of an endogenous system of receptors and cognate ligands, or
endocannabinoids. The role of these putative endogenous cannabinoids and their
receptors in immune cell function has yet to be fully explored, although it has
been postulated that they may be involved in homoeostatic regulation of immune
responses. Studies to assess their functional relevance may yield novel insights
into mechanisms and modalities of action by which exogenous cannabinoids such
as THC may perturb the native functionality of these endogenous systems. In
addition, cannabinoid receptor type-specific agonists and antagonists have been
developed, as have synthetic compounds of varying affinity for the CB 1 and CB 2
receptors, that are applicable to assessment of structure–activity relationships in
immune functional responses. The availability of these pharmacological tools has
afforded novel opportunities for evaluating cannabinoid analogs as therapeutic
agents for management of select untoward or aberrant immune responses. Fur-
thermore, availability of cannabinoid receptor type-specific agonists and antago-
nists, and of chemically engineered cannabinoid compounds, may allow for the
identification, characterization, and isolation of additional cannabinoid receptors
that may be operative in activities linked to immune function.
2
Cannabinoids and the Immune System
2.1
Early Studies
Early in vitro and in vivo studies indicated that marijuana as well as cannabinoids
derivative of this plant, particularly THC, had immunosuppressive properties.
These compounds were found to exert a wide range of effects on a variety of
immune functions from a diverse array of immune cell types. Such effects were
observed for immune cells derivative of various rodents and for cell lines exhibiting