Cannabinoids Inhibit T-cells via Cannabinoid Receptor 2 in an in vitro Assay for Graft Rejection, the Mixed Lymphocyte Reaction

Posted on April 19, 2015 by David

“Cannabinoids are known to have anti-inflammatory and immunomodulatory properties.

Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes.

This study tested the capacity of Δ9-tetrahydrocannabinol (Δ9-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation. Both CB2-selective agonists and Δ9-THC significantly suppressed the MLR in a dose dependent fashion…

Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients.

Cannabinoids were reported to have effects on immune responses as early as the 1970s, but the basis for this activity was not understood until the cannabinoid receptors were cloned

Ideally, the anatomically disparate expression of CB1 and CB2 would allow for the use of compounds selective for CB2, and thus eliminate the unwanted psychoactive effects from CB1 activation, while maintaining the anti-inflammatory and immunosuppressive properties.

CB2-selective cannabinoids have been proposed as possible candidates to block graft rejection.

The results presented in this paper show that Δ9-THC, a mixed CB1/CB2 agonist, and two CB2-selective agonists can inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ and skin graft rejection.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864984/

Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells.

Posted on April 17, 2015 by David

“Cannabidiol (CBD), the main non-psychoactive cannabinoid, has been previously shown by us to ameliorate clinical symptoms and to decrease inflammation in myelin oligodendrocyte glycoprotein (MOG)35-55-induced mouse experimental autoimmune encephalomyelitis model of multiple sclerosis as well as to decrease MOG35-55-induced T cell proliferation and IL-17 secretion. However, the mechanisms of CBD anti-inflammatory activities are unclear.

We found that CBD leads to upregulation of CD69 and lymphocyte-activation gene 3 (LAG3) regulatory molecules on CD4+CD25-accessory T cells. This subtype of CD4+CD25-CD69+LAG3+ T cells has been recognized as induced regulatory phenotype promoting anergy in activated T cells.

Indeed, we observed that CBD treatment results in upregulation of EGR2 (a key T cell anergy inducer) mRNA transcription in stimulated TMOG cells. This was accompanied by elevated levels of anergy promoting genes such as IL-10 (anti-inflammatory cytokine), STAT5 (regulatory factor), and LAG3 mRNAs, as well as of several enhancers of cell cycle arrest (such as Nfatc1, Casp4, Cdkn1a, and Icos).

Moreover, CBD exposure leads to a decrease in STAT3 and to an increase in STAT5 phosphorylation in TMOG cells, positive and negative regulators of Th17 activity, respectively. In parallel, we observed decreased levels of major histocompatibility complex class II (MHCII), CD25, and CD69 on CD19+ B cells following CBD treatment, showing diminished antigen presenting capabilities of B cells and reduction in their pro-inflammatory functions.

CONCLUSIONS:

Our data suggests that CBD exerts its immunoregulatory effects via induction of CD4+CD25-CD69+LAG3+ cells in MOG35-55-activated APC/TMOG co-cultures. This is accompanied by EGR2-dependent anergy of stimulated TMOG cells as well as a switch in their intracellular STAT3/STAT5 activation balance leading to the previously observed decrease in Th17 activity.”

http://www.ncbi.nlm.nih.gov/pubmed/25880134

Full-text: http://www.jneuroinflammation.com/content/12/1/52

Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites.

Posted on April 17, 2015 by David

“2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation.

Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory.

2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids.

In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions.

This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/25877930

Effects of Cannabinoids on T-cell Function and Resistance to Infection.

Posted on April 17, 2015 by David

“This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of ∆9-THC extracted from the marijuana plant, and synthetic cannabinoids…

The overall conclusion of the studies discussed in this review is that cannabinoids that bind to the CB2 receptor, including ∆9-THC and CB2 selective agonists are immunosuppressive.

The studies provide objective evidence for potentially beneficial effects of marijuana and ∆9-THC on the immune system in conditions where it is desirable to dampen immune responses.

An emerging area of investigation that is reviewed is evidence to support the conclusion that CB2 selective agonists are a new class of immunosuppressive and anti-inflammatory compounds that may have exceptional beneficial effects in a variety of conditions, such as autoimmune diseases and graft rejection, where it is desirable to dampen the immune response without psychoactive effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25876735

http://www.thctotalhealthcare.com/category/autoimmune-disease/

Antagonism of cannabinoid receptor 2 pathway suppresses IL-6-induced immunoglobulin IgM secretion.

Posted on June 11, 2014 by David

“Cannabinoid receptor 2 (CB2) is expressed predominantly in the immune system, particularly in plasma cells, raising the possibility that targeting the CB2 pathway could yield an immunomodulatory effect.

Although the role of CB2 in mediating immunoglobulin class switching has been reported, the effects of targeting the CB2 pathway on immunoglobulin secretion per se remain unclear…

These results uncover a novel function of CB2 antagonists and suggest that CB2 ligands may be potential modulators of immunoglobulin secretion.”

http://www.ncbi.nlm.nih.gov/pubmed/24913620

Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders.

Posted on June 10, 2014 by David

Publication cover image

“Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the “immunocannabinoid” system. This system can be an important signaling pathway for immune modulation.

To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation.

Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity.

The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses”

https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0205111

https://www.ncbi.nlm.nih.gov/pubmed/15845647

Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease.

Posted on June 10, 2014 by David

“The impact of the endogenous cannabinoids (AEA, 2-AG, PEA, and virodamine) on the immune cell expressed cannabinoid receptors (CB1, CB2, TRPV-1, and GPR55) and consequent regulation of immune function is an exciting area of research with potential implications in the prevention and treatment of inflammatory and autoimmune diseases.

Despite significant advances in understanding the mechanisms through which cannabinoids regulate immune functions, not much is known about the role of endocannabinoids in the pathogenesis or prevention of autoimmune diseases.

Inasmuch as CB2 expression on immune cells and its role has been widely reported, the importance of CB1 in immunological disorders has often been overlooked especially because it is not highly expressed on naive immune cells.

Therefore, the current review aims at delineating the effect of endocannabinoids on CB1 receptors in T cell driven autoimmune diseases. This review will also highlight some autoimmune diseases in which there is evidence indicating a role for endocannabinoids in the regulation of autoimmune pathogenesis.

Overall, based on the evidence presented using the endocannabinoids, specifically AEA, we propose that the peripheral CB1 receptor is involved in the regulation and amelioration of inflammation associated with autoimmune diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/24911431

Marijuana can treat autoimmune diseases, scientific study states

Posted on June 9, 2014 by David

“Weed enthusiasts are getting their case for nationwide decriminalization of marijuana bolstered considerably by a new scientific study that promises the controversial plant can treat multiple medical maladies.

Scientists at the University of South Carolina have discovered marijuana’s potential to treat autoimmune diseases — such as arthritis, lupus, colitis and multiple sclerosis — in which chronic inflammation plays a pivotal role.

The Journal of Biological Chemistry published the researchers’ findings that state marijuana’s potential key role in fighting these diseases lies in its capacity to suppress certain immune functions, most particularly inflammation.

The study examined whether marijuana’s main active constituent, tetrahydrocannabinol (THC), could affect DNA through “epigenetic” pathways.

The group of molecules with the capacity to alter DNA and the functioning of genes it controls is collectively referred to as the epigenome. It includes a group of molecules called histones, which are responsible for inflammation, both beneficial and harmful.

The research team, led by Mitzi Nagarkatti, Prakash Nagarkatti and Xiaoming Yang, found that THC can, indeed, affect DNA expression through epigenetic pathways by altering histones.

As recreational and medical use of marijuana become more acceptable in developed countries, more research is being conducted and more potential health applications are being uncovered.

Marijuana already has a variety of medical uses including treatment of chronic pain, nausea, vomiting and the wasting syndrome experienced by some AIDS patients.”

http://atlantadailyworld.com/2014/06/05/marijuana-can-treat-autoimmune-diseases-scientific-study-states/

Marijuana could treat autoimmune diseases: study

Posted on June 9, 2014 by David

“The drug has potential to work on chronic inflammation, found in disease like arthritis, lupus, colitis and MS. It may work by suppressing immune functions.

New findings suggest marijuana’s potential key role in fighting autoimmune diseases lies in its capacity to suppress certain immune functions, notably inflammation.

Building the case for the most widely used illicit drug in developed countries, researchers from the University of South Carolina have discovered marijuana’s potential to treat autoimmune diseases in which chronic inflammation plays a pivotal role.”

http://www.nydailynews.com/life-style/health/marijuana-treat-autoimmune-diseases-study-article-1.1816609

More Evidence Pot Treats Auto-Immune Diseases

Posted on June 9, 2014 by David

“Researchers at the University of South Carolina have another clue as to why patients with auto-immune diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, Crohn’s and celiac disease sometimes respond to medical marijuana therapies, according to Science World Reports.

The main active ingredient in pot, THC, regulates gene expression in immune cells, effectively switching off runaway inflammation at the DNA level.

The researchers used mice cells in vivo and the results suggest that “THC activates the expression of a subset of genes while suppressing the expression of another subset of genes.” The net result is less inflammatory response, which can severely damage and kill cells.

Autoimmune diseases involve an abnormal immune response of the body, causing immune cells to attack healthy cells instead of pathogens. Autoimmune diseases — a collection of about 80 diseases — are the 10th leading cause of death of women in all age groups up to 65 years old.

Despite the safety and efficacy of medical cannabis, providers remain under attack across America. California senators Barbara Boxer and Dianne Feinstein currently support the war on pot patients and providers. The Drug Policy Alliance has started a new campaign today to help citizens lobby Senators to defund the war on medical marijuana.”

http://www.eastbayexpress.com/LegalizationNation/archives/2014/06/03/more-evidence-pot-treats-auto-immune-diseases