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 cells.^{33, 74}

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 mitogens^j 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, 155}

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

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

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 conditions.

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

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 aversive⁹⁵

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.

Anti-inflammatory Effects

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 been established.

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 system.

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 diseases.

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

Table 2.8 Historical comparisons between cannabinoids and opiates

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 uses.

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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