Cells of the Immune System
The various organs of the immune system are positioned throughout the
body and include bone marrow, thymus, lymph nodes and spleen. The cells
of the immune system consist of white blood cells, or leukocytes, which
are formed in the bone marrow from stem cells so-called because a great
variety of cells descend from them (see below). There are two kinds
of leukocytes: Lymphocytes and phagocytes. Lymphocytes consist
of B cells, T cells,h and natural killer cells (NK), and
the major phagocytes include monocytes, macrophages and neutrophils.
Phagocytes have many important roles in the immune response,
but most significantly they initiate these responses by engulfing and
digesting foreign substances (e.g., bacteria, viruses, foreign proteins),
or antigens, that enter the body. Once digested, the antigen is exposed
to specialized Iymphocytes (i.e., B cells and T cells) so that antibodies
and effector T cells can be produced to help destroy any remaining antigens
in the body. Antibodies are proteins produced by B cells that
bind to antigens and promote antigen destruction. effector T cells include
killer T cells which attack and kill antigen laden cells, and helper
T cells, which secrete special proteins called cytokines that promote
antigen elimination. Natural killer cells are specialized Iymphocytes
that are also activated by antigen to either kill infected targets or
secrete immunoregulatory cytokines.
h The B and T refer to where the cells mature, either in
the bone marrow (B) or thymus (T).
The CB2 receptor gene, which is not expressed in the brain,
is particularly abundant in immune tissues, with an expression level
10-100 times higher than that of CB1 In spleen and tonsils,
the CB2 mRNAi content is equivalent to that of
CB1 mRNA in the brain.48 The rank order, from
high to low, of CB2 mRNA levels in immune cells is B-cells
> natural killer cells >> monocytes > polymorphonuclear
neutrophil cells > T8 cells in T4 cells. In tonsils, the CB2
receptors appear to be restricted to B-lymphocyte-enriched areas. In
contrast, CB1 receptors are mainly expressed in the central
nervous system and, to a lower extent, in several peripheral tissues
such as adrenal gland, heart, lung, prostate, uterus, ovary, testis,
bone marrow, thymus and tonsils.
Cannabinoid Receptors and Intracellular Action in Immune Cells
CB2 appears to be the predominant gene expressed in resting
leukocytes.78, 112 The level of CB1 gene activity
is normally low in resting cells but increases with cell activation.32
Thus the CB1 receptor might be important only when immune
responses are stimulated, but the physiological relevance of this observation
remains to be determined. Some of the cannabinoid effects observed in
immune systems, especially at high drug concentrations, are likely mediated
through non-receptor mechanisms, but these have not yet been identified.4
Ligand binding to either the CB1 or CB2 receptors
inhibits adenylate cyclase, an enzyme that is responsible for cAMP production,
and is, thus, an integral aspect of intracellular signal transduction
(see figure 2.3).53, 79, 91, 122, 139, 151, 167 Increases
in intracellular cAMP concentrations lead to immune enhancement, while
decreases lead to an inhibition of immune responses.77 Cannabinoids
inhibit the rise in intracellular cAMP that normally results from leukocyte
activation, and this might be the pathway through which cannabinoids
suppress immune cell functions.28, 74, 167 In addition, cannabinoids
activate other molecular pathways such as the nuclear factor-kB pathway
and therefore these signals might be modified in drug treated immune
i After a gene is transcribed it is often spliced
and modified into mRNA, or message RNA. The CB-2 mRNA is the gene "message"
that moves from the cell nucleus into the cytoplasm where it will be
translated into the receptor protein.
T and B Cells
When stimulated by antigen, lymphocytes (see box on Cells of the Immune
System) first proliferate and then mature or differentiate to become
potent effector cells, such as B cells that release antibodies or T
cells that release cytokines. The normal T cell proliferation that is
seen when human lymphocytes and mouse splenocytes (spleen cells) are
exposed to antigens and mitogensj can be inhibited
by THC, 11-OH-THC, cannabinol, and 2-AG, as well as synthetic cannabinoid
agonists such as CP 55,940, WIN 55,212 and HU-210 61, 89, 93, 99,
127, 155 In contrast, one study testing anandamide revealed little
or no effect on T-cell proliferation.93
However, these drug effects are variable, and depend on experimental
conditions such as the experimental drug dose used, mitogen used, percent
of serum in the culture, and timing of cannabinoid drug exposure. In
general, lower doses of cannabinoids increase proliferation while higher
doses suppress proliferation. Doses that are effective in suppressing
immune function are typically greater than 10 µM in cell culture
studies and greater than 5 mg/kg in whole animal studies.85
By comparison, at 0.05 mg/kg, people will experience the full psychoactive
effects of THC; however, because of their high metabolic rates, small
rodents frequently require drug doses that are 100-fold higher than
doses needed for humans to achieve comparable drug effects. Thus, the
immune effects of doses of cannabinoids higher than those ever experienced
by humans, should be interpreted with caution.89, 93, 93, 127,
As with T cells, B cell proliferation can be suppressed by various
cannabinoids, such as THC, 11-OH-THC and 2-AG, but B cell proliferation
is more inhibited at lower drug concentrations than T cell proliferation.89,
93 Conversely, low doses of THC, CP 55,940 and WIN 55,212-2 increase
B-cell proliferation in cultured human cells exposed to mitogen.35
This effect possibly involves the CB2 receptor, because the
effect appears to be the same when the CB1 receptor was blocked
by the antagonist, SR-141716A (which does not block the CB2
receptor). The reason for the differences in cell responsiveness to
cannabinoids is probably due to differences in cell type and source;
for example, B cells collected from mouse spleen might respond to cannabinoids
somewhat differently than B cells from human tonsils.
jMitogens are substances that stimulate cell division
(mitosis) and cell transformation.
Natural Killer Cells
Repeated injections of relatively low doses of THC (3 mg/kg/day 121
k) or two injections of a high dose (40 mg/kg86) suppress
the ability of natural killer (NK) cells to destroy foreign cells in
rats and mice. THC can also suppress natural killer cell cytolytic activity
in cell cultures; 11-OH-THC, is even more potent.86 In contrast,
THC doses below 10µM had no effect on natural killer cell activity
in mouse cell cultures.98
Macrophages perform various functions including phagocytosis (ingestion
and destruction of foreign substances), cytolysis, antigen presentation
to lymphocytes, and production of a variety of active proteins involved
in destroying microorganisms, tissue repair and modulation of immune
cells. Those functions can be suppressed by THC doses similar to those
capable of modulating lymphocyte functions (see above).88, 109
Cytokines are proteins produced by immune cells. When released from
the producing cell they can alter the function of other cells they come
in contact with. In a sense, they are like hormones. Thus, cannabinoids
can either increase or decrease cytokine production depending upon experimental
Certain cytokines, such as interferon-
and interleukin-2 (IL-2) are produced by T helper-1 (Th1) cells. These
cytokines help to activate cell-mediated immunity and the killer cells
that eliminate microbes from the body (see Box on cells of the immune
system). When injected into mice, THC suppresses the production of those
cytokines that modulate the host response to infection (see below).115
Cannabinoids also modulate interferons induced by viral infection,21
as well as other interferon inducers.85 Furthermore, in human
cell cultures, interferon production can be increased by low concentrations,
but decreased by high concentrations of either THC or cannabidiol. 6
In addition to Th1 cytokines, cannabinoids also modulate the production
of cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF),
and interleukin-6 (IL-6). 145, 176 At 8 mg/kg, THC can increase
the in vivo mobilization of serum acute phase cytokines including
IL-1, TNF, and IL-6.90 Finally, although these studies suggest
that cannabinoids can induce an increase in cytokines, other studies
suggest that they can also suppress cytokine production.85
The different results might be due to different cell culture conditions
or because different cell lines were studied.
k While 3 mg/kg would be a high dose for humans (see
table 3.1); in rodents, it is a low dose for immunological effects,
and a moderate dose for behavioral effects.
Antibody production is an important measure of humoral immune function
as contrasted with cellular (cell-mediated immunity). Antibody production
can be suppressed in mice injected with relatively low doses of THC
(>5 mg/kg) or HU210 (>0.05 mg/kg) and in mouse spleen cell cultures
exposed to a variety of cannabinoids, including THC, 11-OH-THC, cannabinol,
cannabidiol, CP 55,940, or HU-210.5, 6, 61, 78, 79, 84, 85, 142,
164 However, the inhibition of antibody response by cannabinoids
was only observed when antibody-forming cells were exposed to T cell-dependent
antigens (the responses require functional T cells and macrophages as
accessory cells). Conversely, antibody responses to several T cell-independent
antigens were not inhibited by THC, suggesting that the B cell is relatively
insensitive to inhibition by cannabinoids.142
Resistance To Infection In Animals Exposed To Cannabinoids
Bacterial infections evaluated in mice demonstrated that THC can suppress
resistance to infection, although the effect depends upon the dose and
timing of drug administration. Mice pre-treated with THC (8 mg/kg) one
day prior to infection with a sublethal dose of the pneumonia-causing
bacteria, Legionella pneumophilia, and then treated again one
day after the infection with THC, developed symptoms of cytokine-mediated
septic shock and died; control mice that were not pre-treated with THC
became immune to repeated infection and survived the bacterial challenge.90
If only one injection of THC was given or doses less than 5 mg/kg were
used, all of the mice survived the initial infection, but failed to
survive a subsequent challenge with a lethal dose of the bacteria; hence
these mice failed to develop immune memory in response to the initial
sublethal infection.87 Note that these are very high doses,
and are considerably higher than doses experienced by marijuana users
(see figure 3.1).115 In rats, doses of 4.0 mg/kg THC are
Few studies have been done to evaluate the effect of THC on viral infections,
and this is an area that needs further study.20 Compared
to healthy animals, THC might have greater immunosuppressive effects
in animals whose immune systems are severely weakened. For example,
a very high dose of THC (100 mg/kg) given twice, two days before and
after herpes simplex virus infection, was shown to be a co-factor with
herpes simplex virus in enhancing the progression to death in an immunodeficient
mouse model infected with a leukemia virus.85 However, THC
given as a single dose (100 mg/kg) two days before herpes simplex virus
infection did not promote the progression to death in these animals.
Hence, whether THC is immunosuppressive likely depends on the timing
of THC exposure relative to an infection.
As discussed above, cannabinoid drugs can modulate the production of
cytokines, which are central to inflammatory processes in the body.
In addition, several studies have shown directly that cannabinoids can
be anti-inflammatory. For example, in rats with autoimmune encephalomyelitis
(an experimental model used to study multiple sclerosis), cannabinoids
were shown to attenuate the signs and the symptoms of central nervous
system damage.100, 172 (Some believe that nerve damage associated
with multiple sclerosis is caused by an inflammatory reaction.) Likewise,
the cannabinoid, HU-211, was shown to suppress brain inflammation that
resulted from closed head injury 146 or infectious meningitis
7 in studies on rats. HU211 is a synthetic cannabinoid that
does not bind to cannabinoid receptors, and is not psychoactive,7
thus, without direct evidence, the effects of marijuana cannot be assumed
to include those of HU-211. CT-3, another atypical cannabinoid, suppresses
acute and chronic joint inflammation in animals.178 It is
a nonpsychoactive, synthetic derivative of 11-THC-oic acid (a breakdown
product of THC), and does not appear to bind to cannabinoid receptors.
129 Cannabichromene, a cannabinoid found in marijuana, has
also been reported to have anti-inflammatory properties.173
No mechanism of action for possible anti-inflammatory effects of cannabinoids
has been identified and the effects of these atypical cannabinoids and
effects of marijuana are not yet established.
It is interesting to note that two reports of cannabinoid-induced analgesia
are based on the ability of the endogenous cannabinoids, anandamide
and PEA, to reduce pain associated with local inflammation that was
experimentally induced by subcutaneous injections of dilute formalin.22,
73 Both THC and anandamide can increase serum levels of ACTH and
corticosterone in animals.169 Those hormones are involved
in regulating many responses in the body, including those to inflammation.
The possible link between experimental cannabinoid-induced analgesia
and reported anti-inflammatory effects of cannabinoids is important
for potential therapeutic uses of cannabinoid drugs, but has not yet
Conclusions regarding effects on immune system
Based on cell culture and animal studies, cannabinoids have been established
as immunomodulators - that is, they increase some immune responses and
decrease others. The variable responses depend upon experimental factors
such as drug dose, timing of delivery, and type of immune cell examined.
Cannabinoids affect multiple cellular targets within the immune system
and a variety of effector functions. Many of the effects noted above
appear to occur at
concentrations of > 5 µM in vitro and > 5 mg/kg
in vivo.l By comparison, a 5 mg injection of THC into
a person (about 0.06 mg/kg) is enough to produce strong psychoactive
effects. It should be emphasized, however, that little is known about
the effects of chronic low dose exposure to cannabinoids on the immune
Another issue in need of further clarification involves the potential
usefulness of cannabinoids as therapeutic agents in inflammatory diseases.
Glucocorticoids have historically been used for these diseases, but
non-psychotropic cannabinoids potentially have fewer side effects and
might thus offer an improvement over glucocorticoids in treating inflammatory
Conclusions and Recommendations
Following the progress of the past fifteen years in understanding the
effects of cannabinoids, research over the next decade is likely to
reveal even more. It is interesting to compare how little we know about
the cannabinoids with how much we know about the opiates (table 2.8).
This table, in fact, suggests good reason for optimism about the future
of cannabinoid drug development. Now that many of the basic tools of
cannabinoid pharmacology and biology have been developed, one can expect
to see rapid advances that can begin to match what is known for opiate
systems in the brain.
Despite the tremendous progress in understanding the pharmacology and
neurobiology of brain cannabinoid systems, this field is still in its
early developmental stages. A key focus for future study is the neurobiology
of endogenous cannabinoids. Establishing the precise brain localization
- i.e.,., in which cells and where in those cannabinoids are found,
cellular storage and release mechanisms, and uptake mechanisms will
be crucial in determining the biological role of this system. Technology
that will be crucial in establishing the biological significance of
these systems will be broad based and include such research tools as
the transgenic, or gene knockout mice, as have already been accomplished
for various opioid receptor types.26 In 1997, both CB1
and CB2 receptor knockout mice were generated by a team of
scientists at NIH, and a group in France has developed another strain
of CB1 in receptor knockout mice.92
lIn vitro studies are those in which animal cells or
tissue are removed and studied outside the animal; in vivo studies are
those in which experiments are conducted in the whole animal.
Table 2.8 Historical comparisons between cannabinoids and opiates
|Comparisons between cannabinoids and opiates
|Discovery of receptor existence
||1988 (Howlett and Devane)36, 40
||1973 (Pert and Snyder, Terenius, and Simon)123, 149, 162
|Identification of receptor antagonist
||1994 SR141716A (Rinaldi- Carmona)132
||pre- 1973 Naloxone
|Discovery of 1st endogenous ligand
||1992 Anandamide (Devane And Mechoulam)37
||1975 Met- and Leu-enkephalin (Hughes et al)70
|1st Receptor cloned
||1990 (Matsuda) 107
||1992 (Evans et al. and Kieffer et al.)41, 82
|Natural functions of cannabinoid / opiate systems
||Pain, reproduction, mood, movement, and others
There are several research tools that will greatly aid such investigations
- in particular, a greater selection of agonists and antagonists that
permit discrimination between the activation of CB1 versus CB2 receptors;
hydrophilic agonists (that can be delivered to animals or cells more
effectively than hydrophobic compounds). In the area of drug development,
future progress should continue to provide more specific agonists and
antagonists for CB1 and CB2 receptors, with varying potential for therapeutic
There are certain areas that will provide keys to a better understanding
of the potential therapeutic value of cannabinoids. For example, basic
biology indicates a role for cannabinoids in pain and control of movement,
which is consistent with a possible therapeutic role in these areas.
The evidence is relatively strong for the treatment of pain, and intriguingly,
although less well-established, for movement disorders. The neuroprotective
properties of cannabinoids might prove therapeutically useful, although
it should be noted that this is a new area and other, better studied,
neuroprotective drugs have not yet been shown to be therapeutically
useful. Cannabinoid research is clearly relevant not only to drug abuse,
but also to
understanding basic human biology. Further, it offers the potential
for the discovery and development of new, therapeutically useful drugs.
CONCLUSION: At this point, our knowledge about the biology of
marijuana and cannabinoids allows us to make some general conclusions:
Cannabinoids likely have a natural role in pain modulation,
control of movement, and memory.
The natural role of cannabinoids in immune systems is likely multifaceted
and remains unclear.
The brain develops tolerance to cannabinoids.
Animal research demonstrates the potential for dependence, but this
potential is observed under a narrower range of conditions than with
benzodiazepines, opiates cocaine, or nicotine.
Withdrawal symptoms can be observed in animals, but appear to be
mild compared to opiates or benzodiazepines, such as diazepam (Valium
CONCLUSION: The different cannabinoid receptor types found in
the body appear to play different roles in normal physiology. In addition,
some effects of cannabinoids appear to be independent of those receptors.
The variety of mechanisms through which cannabinoids can influence human
physiology underlies the variety of potential therapeutic uses for drugs
that might act selectively on different cannabinoid systems.
RECOMMENDATION: Research should continue into the physiological
effects of synthetic and plant-derived cannabinoids and the natural
function of cannabinoids found in the body. Because different cannabinoids
appear to have different effects, cannabinoid research should include,
but not be restricted to effects attributable to THC alone.
This chapter has summarized recent progress in understanding the basic
biology of cannabinoids, and provides a foundation for the next two
chapters which review studies on the potential health risks (chapter
3) and benefits of marijuana use (chapter 4).
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