ECS & the Immune System

The presence of cannabinoid receptors on immune cells along with anecdotal and historic observation showing strong immunomodulatory effects of cannabis use have led to researching the function and role of these receptors in the context of immunological cell response. The endocannabinoid system modulates the maturation of immune cells in primary lymphatic tissues as well as their effector function like i.e. cytokine secretion. Today the regulatory effect of cannabinoids on T and B lymphocytes, natural killer (NK) cells, macrophages and microglia is undisputed. However, further research is necessary in the future for a better understanding of the underlying processes. Nevertheless, already today one can conclude that cannabinoids should be considered for the treatment of (chronic) inflammatory disorders.

Since the discovery of cannabinoid receptors and their endogenous ligands substantial progress was made in the investigation of physiological functions of the endocannabinoid system on health and disease. The presence of cannabinoid receptors on immune cells along with anecdotal and historic observations showing immunomodulatory effects of cannabis use have led to research of the function and role of these receptors in the context of immunological cell response. Today the effect of cannabimimetic substances on T and B lymphocytes, natural killer (NK) cells, macrophages and microglia is undisputable. However, further research is necessary in the future for a better understanding of the underlying processes. Nevertheless, today one can already conclude that cannabinoids should be considered for the treatment of (chronic) inflammatory disorders like i.e. multiple sclerosis, rheumatoid arthritis, diabetes or allergic asthma.1

Some authors consider both systems to be so closely related that they even speak of the “immuno-cannabinoid system” in scientific publications.4

Cytokines are messenger substances produced by immune cells for the regulation of the immune response. TNF-alpha (tumor necrosis factor alpha) for example belongs to the group of pro-inflammatory cytokines, whereas the interleukins IL-10 (Interleukin-10), IL-4 (Interleukin-4) and IL-11 (Interleukin-11) primarily belong to the group of anti-inflammatory cytokines.

immune_system_eng
Figure 1. The immune system
(adapted from: Klein et al., Pain Res Manage 2001)2

Stem cells mature to competent lymphocytes in primary lymphoid organs such as thymus and bone marrow (BM). The mature lymphocytes migrate to secondary lymphoid organs such as the spleen, lymph node, blood, bronchial lymphatic tissue (BALT), gut-associated lymphatic tissue (GALT) and skin, where they interact with the other main cellular components of the immune system. Foreign antigen induces these cells to produce the various effector functions of immunity, including cell-mediated immunity (CMI) and antibodies, allergy and autoimmunity, chemokines and cytokines such as interferons (IFNs) and tumour necrosis factor (TNF), and neuroimmune hormones such  as endorphins and anandamide.

In the primary lymphatic organs (i.e. thymus, bone marrow) stem cells mature into leucocytes (white blood cells). T cells develop in the thymus, B cells in the bone marrow. B cells produce antibodies that can bind to pathogens and thereby enable the immune system to detect and eliminate these pathogens. T helper cells signal to B cells to produce antibodies and increase the ability of macrophages (another subset of leucocytes) to phagocytose (“eat”) pathogens. T killer cells, along with NK cells (natural killer cells) are killing leucocytes as their name suggests. They destroy cells that i.e. are infected by viruses. Another important subtype of leucocytes is the one of dendritic cells. When pathogens invade the organism dendritic cells present appropriate antigens (antigens are proteins or other components of phagocytized pathogens) to T helper cells, and thereby signal the type of pathogens involved and how to be destroyed. Thereupon, a complex orchestrated immune response is initiated (i.e. by increased production / mitotic cell division of the necessary immune cells). Microglia cells perform similar tasks in the brain like macrophages or dendritic cells. Mast cells, eosinophil and basophil granulocytes contain messenger substances like histamine and heparin that are immediately secreted upon identification of pathogens. As a result, an intense inflammatory response is initiated (reddening, itching/pain, swelling) that indicates – along with other chemotactic signals – other immune cells to migrate to the place of action for support. Regulatory T cells ensure the termination of the immune response at a suitable time point.3

During maturation of immune cells the development of cells recognizing foreign antigens is favored and the one of recognizing self-antigens is suppressed in order to prevent autoimmunity. Maturation in these organs is regulated by hormones like corticosteroids (stress hormones of the adrenal cortex) and cytokines and can be modulated by drugs like cannabinoids. Fully matured lymphocytes (B, T and NK cells) exit the thymus and bone marrow and migrate to secondary lymphatic organs such as the spleen and lymph nodes. The immune response is initialized in these tissues upon detection of antigens or microbes. Each of the described cellular interactions is regulated by hormones and cytokines so that pharmaceuticals like cannabinoids can intervene at this point as secondary modulators.

In a review1 published in 2005 in the Journal of Neuroimmunology the authors summarized some of the effects of phytocannabinoids (link) that had been established thus far. The following table is taken from this review:

Table 1: Effects of cannabinoids on cytokine production


CytokineSystemDrug Reference
Increase in cytokine production
IL-1In vitro mouse macrophages THC Zhu et al., 1994
In vivo mouse serum THC Klein et al., 1993
In vitro mouse macrophagesTHC Newton et al., 1998
TNF In vitro human monocytes THC Shiver et al., 1994
In vivo mouse serum THC Klein et al., 1998
In vitro mouse macrophages THC Newton et al.,1998
IL-4 In vitro human T cell dendritic cell co-culture THC Yuan et al., 1993
IL-6 In vivo mouse Serum THC klein et al., 1993
IL-12 In vitro/ex vivo mouse macrophages CBD Sacerdote et al., 2005
Decrease in cytokine production
IFN-Ɣ Ex vivo mouse spleen THC Blanchard et al., 1986
In vitro human NK cells THC Srivastava et al., 1998
In vitro mouse splenocytes THC Blanchard et al., 1986
In vitro human PBMC THC/CBD Watzl et al.,1991
In vitro human T cell dendritic cell co-culture THC Yuan et al., 2002
In vitro mouse splemocytes THC Newton et al., 1998
TNF Macrophage cell lines THC Zheng et al.,1992
In vitro human NK cells THC Kusher et al., 1994
In vitro human PBMC CBD Watzl et al.,1991
In vitro human NK cells THC Srivastava et al.,1998
IL-1 In vitro human PBMC CBD Watzl et al.,1991
IL-2 In vitro mouse spleen THC Nakano et al., 2005
IL-10 In vitro human T cells THC/CBD Srivastava et al., 1998
In vitro/ex vivo mouse macrophages CBD sacerdote et al., 2005
IL-12 In vitro mouse splentocytes/macrophages THC Newton et al., 1998
THC- Δ9-trans-Tetrahydrocannabinol; CBD - cannabidiol; PBMC - peripheral blood monocytes. (aus: Croxford JL, Yamamura T., J Neuroimmunol. 2005)

The authors hypothesize that the CB1-mediated effect influences T helper cell activity via the hypothalamus-hypophysis-adrenal-stress-axis (HPA-axis) as a result of corticosteroid secretion. Moreover, CB2-receptors expressed on immune cell subpopulations might be involved in the modulation of the cytokine profile via G-protein coupled secondary messenger signals (see Fig. 2), which impacts the relative maturation of T cell subtypes. Immune cells often express new gene products upon stimulation with antigens and other bioactive substances. This also seems to be the case upon stimulation of cannabinoid receptors.

The endocannabinoid system and cell function. An influx of Ca2+ activates phospholipases (PL), which drive the conversion of membrane arachidonic acid (AA) to endocannabinoids such as anandamide (ANA), 2-arachidonoylglycerol (2-AG), and 2-arachidonylglyceryl ether (2-AGE). The endocannabinoids can be taken up and metabolized by fatty acid amide hydrolase (FAAH) or can bind to CB1 or CB2. These are G protein-coupled receptors (GPCR) capable of signalung through G protein subunits, Gα, -β, and -Γ, leading to a modulation of nitric oxide (NO) and adenylyl cyclase (AC). In neurons, this signaling can lead to a change in K+ and Ca2+ currents and secretion of transmitters such as Γ-aminobutyric acid (GABA). In addition, CB1 and CB2 signaling can lead to the activation of many other factors, including PLC, protein kinase C (PKC), nuclear factor-ϰB (NF-ϰB), extracellular signal-regulated protein kinase (ERK), focal adhesion kinase (FAK), steroid receptor coactivator (Src), mitogen-activated protein kinase (MAPK), and MAPK kinase (MEK.)
the_endocannabinoid_system_and_cell_function
Figure 2. Second messenger signals upon cannabinoid receptor stimulation by example of a neuronal cell; from: Klein et al., 20034

In summary, endocannabinoid signaling pathways may act as tonic regulatory bodies in lymphatic tissues that limit spontaneous activation of effector immune cells.

The inhibiting effect of cannabinoids on the function of the immune system seems to be temporary however. Meaning that in case of an infection the inhibitory effect can be overcome. This effect seems to be supported by a diminished expression of cannabinoid receptors upon activation of several immune cell subtypes. Furthermore, despite minimal side-effects, the transient nature of the effect of cannabinoids on immune cell function pleads for a long-term administration of cannabinoid medicine. Recent studies further suggest different effects of synthetic, plant-based and endogenous cannabinoids on the immune system that are dose-dependent. Endocannabinoids were associated with the induction of cytokines as well as the migration (chemotaxis, adhesion) of immune cells, i.e. of B cells.1

With this said it is desirable that in the near future immunologists will investigate the promising effects of the endocannabinoid system and plant-based ligands for the treatment of immune system disorders further, in order to enable more patients to benefit from the therapeutic potential of cannabinoid medicine that has only few side effects.

[1] Croxford JL, Yamamura T. Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases? doi:10.1016/j.jneuroim.2005.04.023

[2] Klein TW, Newton CA, Friedman H. Cannabinoids and the immune system. Pain Res Manag. 2001;6(2):95-101. http://www.ncbi.nlm.nih.gov/pubmed/11854771.

[3] Immunobiology, 5th edition. The Immune System in Health and Disease. Charles A Janeway, Jr, Paul Travers, Mark Walport, and Mark J Shlomchik. ISBN-10: 0-8153-3642-X.

[4] Klein TW, Newton C, Larsen K, et al. The cannabinoid system and immune modulation. J Leukoc Biol. 2003;74(4):486-496. doi:10.1189/jlb.0303101