Category Archives: Autoimmune Disease

Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis.

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Biochemical Pharmacology

“The gut microbiota plays a fundamental role on the education and function of the host immune system.

Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the immune system homeostasis.

The cannabinoid system and related bioactive lipids participate in multiple central and peripheral physiological processes that affect metabolic, gastrointestinal and neuroimmune regulatory mechanisms displaying a modulatory role and contributing to the maintenance of the organism’s homeostasis.

In this review, we gather the knowledge on the gut microbiota-endocannabinoids interactions and their impact on autoimmune disorders such as inflammatory bowel disease, rheumatoid arthritis and particularly, multiple sclerosis (MS) as the best example of a CNS autoimmune disorder.

Furthermore, we contribute to this field with new data on changes in many elements of the cannabinoid system in a viral model of MS after gut microbiota manipulation by both antibiotics and probiotics.

Finally, we highlight new therapeutic opportunities, under an integrative view, targeting the eCBS and the commensal microbiota in the context of neuroinflammation and MS.”

https://www.ncbi.nlm.nih.gov/pubmed/30171835

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303630

Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells.

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“Multiple sclerosis (MS) is a chronic debilitating autoimmune disease without a cure. While the use of marijuana cannabinoids for MS has recently been approved in some countries, the precise mechanism of action leading to attenuate neuroinflammation is not clear. We used experimental autoimmune encephalomyelitis (EAE), a murine model of MS, to explore the anti-inflammatory properties of cannabidiol (CBD), a non-psychoactive cannabinoid. Treatment with CBD caused attenuation of EAE disease paradigms as indicated by a significant reduction in clinical scores of paralysis, decreased T cell infiltration in the central nervous system, and reduced levels of IL-17 and IFNγ. Interestingly, CBD treatment led to a profound increase in myeloid-derived suppressor cells (MDSCs) in EAE mice when compared to the vehicle-treated EAE controls. These MDSCs caused robust inhibition of MOG-induced proliferation of T cells in vitro. Moreover, adoptive transfer of CBD-induced MDSCs ameliorated EAE while MDSC depletion reversed the beneficial effects of CBD treatment, thereby conclusively demonstrating that MDSCs played a crucial role in CBD-mediated attenuation of EAE. Together, these studies demonstrate for the first time that CBD treatment may ameliorate EAE through induction of immunosuppressive MDSCs.”

https://www.ncbi.nlm.nih.gov/pubmed/30123217

“In conclusion, we have demonstrated that the mitigation of EAE with CBD comes from its ability to target a range of anti-inflammatory pathways, including (i) induction of anti-inflammatory MDSCs and (ii) decrease in pro-inflammatory and induction of anti-inflammatory cytokines. Because CBD is non-psychoactive, our studies suggest that CBD may constitute an excellent candidate for the treatment of MS and other autoimmune diseases. Our studies provide further evidence of the importance of MDSCs and that manipulation of such cells may constitute novel therapeutic modality to treat MS and other autoimmune diseases.”

https://www.frontiersin.org/articles/10.3389/fimmu.2018.01782/full

EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis.

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Elsevier

“Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune disease characterized by vascular, immunological, and fibrotic abnormalities.

The etiology of SSc is unknown, but there is growing evidence that dysfunction of the endocannabinoid system (ECS) plays a critical role in its development.

Since the semi-synthetic cannabinoquinoid VCE-004.8 could alleviate bleomycin (BLM)-induced skin fibrosis, we have investigated an oral lipid formulation (EHP-101) of this dual PPARγ/CB2 receptors activator for the prevention of skin- and lung fibrosis and of collagen accumulation in BLM challenged mice.

Taken together, these data provide a rationale for further developing VCE-004.8 as an orally active agent to alleviate scleroderma and, possibly, other fibrotic diseases as well.”

 https://www.ncbi.nlm.nih.gov/pubmed/30076848
https://www.sciencedirect.com/science/article/abs/pii/S0006295218303174

Emerging strategies targeting cb2 cannabinoid receptor: biased agonism and allosterism.

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Biochemical Pharmacology

“During these last years, the CB2 cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB2 agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB2 receptor may offer new avenues for the development of improved CB2 receptor-targeted therapies. Although there has been some exploration of CB1 receptor activation by new CB1 allosteric or biased-signaling ligands, the CB2 receptor is still at initial stages in this domain. In an effort to understand the molecular basis behind these pharmacological approaches, we have analyzed and summarized the structural data reported so far at CB2 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/30055149
https://www.sciencedirect.com/science/article/abs/pii/S0006295218302995

Endocannabinoid system in systemic lupus erythematosus: first evidence for a deranged 2-arachidonoylglycerol metabolism.

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The International Journal of Biochemistry & Cell Biology

“The endocannabinoid (eCB) system plays a key role in many physiological and pathological conditions and its dysregulation has been described in several rheumatological and autoimmune diseases. Yet, its possible alteration in systemic lupus erythematosus (SLE) has never been investigated.

Here, we aimed filling this gap in plasma and peripheral blood mononuclear cells (PBMCs) of patients with SLE and age- and sex- matched healthy subjects (HS).

In conclusion, our results demonstrate, for the first time, an alteration of eCB system in SLE patients. They represents the first step toward the understanding of the role of eCB system in SLE that likely suggest DAGL and 2-AG as potential biomarkers of SLE in easily accessible blood samples.

Our data provides proof-of-concept to the development of cannabis-based medicine as immune-modulating agents.”

https://www.ncbi.nlm.nih.gov/pubmed/29655919

https://www.sciencedirect.com/science/article/pii/S1357272518300852?via%3Dihub

Clinical response to Nabiximols correlates with the down-regulation of immune pathways in Multiple Sclerosis.

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European Journal of Neurology

“Nabiximols (Sativex® ) is a cannabinoid-based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS).

The aim of the study is to investigate the effect of the administration of Nabiximols on blood transcriptome profile of MS patients and to interpret it in the context of pathways and networks.

Our findings support the immunomodulatory activity of cannabinoids in MS patients. Further studies in more specific cell types are needed to refine these results.”

https://www.ncbi.nlm.nih.gov/pubmed/29528549

http://onlinelibrary.wiley.com/doi/10.1111/ene.13623/abstract

“Cannabinoid compounds suppress immune function, and while this could compromise one’s ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases.” https://www.ncbi.nlm.nih.gov/pubmed/29512125
“Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923447/

Evaluation of Marijuana Compounds on Neuroimmune Endpoints in Experimental Autoimmune Encephalomyelitis.

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Current Protocols in Toxicology

“Cannabinoid compounds refer to a group of more than 60 plant-derived compounds in Cannabis sativa, more commonly known as marijuana. Exposure to marijuana and cannabinoid compounds has been increasing due to increased societal acceptance for both recreational and possible medical use. Cannabinoid compounds suppress immune function, and while this could compromise one’s ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases. It is critical, therefore, to understand the effects and mechanisms by which cannabinoid compounds alter immune function, especially immune responses induced in autoimmune disease. Therefore, this unit will describe induction and assessment of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and its potential alteration by cannabinoid compounds. The unit includes three approaches to induce EAE, two of which provide correlations to two forms of MS, and the third specifically addresses the role of autoreactive T cells in EAE.”

https://www.ncbi.nlm.nih.gov/pubmed/29512125

http://onlinelibrary.wiley.com/doi/10.1002/cptx.43/abstract

Cannabidiol Limits T Cell–Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation

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“Cannabidiol (CBD) is a nonpsychoactive ingredient of marijuana (Cannabis sativa).

Collectively, our study demonstrates that CBD treatment markedly attenuates autoimmune myocarditis and improves myocardial dysfunction and heart failure primarily by its antiinflammatory and antifibrotic effects.

These results, coupled with the proven safety of CBD in human clinical trials and its current orphan drug approval by the FDA for different neurological disorders, suggest that it has tremendous therapeutic potential in the therapy of myocarditis with different etiologies and various autoimmune disorders. The latter is also supported by beneficial effects of CBD in preventing graft versus host disease after allogeneic hematopoietic cell transplantation in a recent phase II human study, as well as in mice with arthritis. Attenuation of the T cell–mediated injury by CBD also suggests that it may have therapeutic utility in management of organ transplantation/rejection.

In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.”

https://www.ncbi.nlm.nih.gov/pubmed/26772776

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004721/

http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/16_007_Lee.pdf

History of marijuana use does not affect outcomes on the liver transplant waitlist.

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“Data are limited on marijuana use and its impact on liver transplant (LT) waitlist outcomes.

We aimed to assess the risk of waitlist mortality/delisting and likelihood of LT among prior marijuana users, and to determine the prevalence and factors associated with marijuana use.

Unlike illicit drug use, marijuana use was not associated with worse outcomes on the LT waitlist.”

https://www.ncbi.nlm.nih.gov/pubmed/29319619

https://insights.ovid.com/crossref?an=00007890-900000000-96711

https://journals.lww.com/transplantjournal/Abstract/onlinefirst/History_of_marijuana_use_does_not_affect_outcomes.96711.aspx

“Do Cannabinoids have a therapeutic role in transplantation? Transplantation is one critical area of medicine that requires the use of immunosuppressants. Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923447/
“The history of donor cannabis smoking does not appear to affect early and mid-term outcomes after lung transplantation (LTx) and potentially improve the donor pool. As it does not seem to negatively affect the outcomes after LTx, it should not be per se considered a contraindication for lung donation.” https://www.ncbi.nlm.nih.gov/pubmed/28077504
“THC In Marijuana Delays Organ Transplant Rejection In Mice. A new study suggests the active ingredient in marijuana delays the rejection of incompatible organs in mice.” http://www.iflscience.com/health-and-medicine/thc-marijuana-may-delay-organ-transplant-rejection/
“Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541500/
“Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation. CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation.” http://pubmedcentralcanada.ca/pmcc/articles/PMC5004721/
“Could CANNABIS help transplant patients? Drug ‘delays rejection of organs by slowing the immune system’s attack'” http://www.dailymail.co.uk/health/article-3279752/Could-CANNABIS-help-transplant-patients-Drug-delays-rejection-organs-slowing-immune-s-attack.html

Effects of chronic Δ9-tetrahydrocannabinol treatment on Rho/Rho-kinase signalization pathway in mouse brain.

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Saudi Pharmaceutical Journal

“Δ9-Tetrahydrocannabinol (Δ9-THC) shows its effects by activating cannabinoid receptors which are on some tissues and neurons. Cannabinoid systems have role on cell proliferation and development of neurons. Furthermore, it is interesting that cannabinoidsystem and rho/rho-kinase signalization pathway, which have important role on cell development and proliferation, may have role on neuron proliferation and development together. Thus, a study is planned to investigate rhoA and rho-kinase enzyme expressions and their activities in the brain of chronic Δ9-THC treated mice. One group of mice are treated with Δ9-THC once to see effects of acute treatment. Another group of mice are treated with Δ9-THC three times per day for one month. After this period, rhoA and rho-kinase enzyme expressions and their activities in mice brains are analyzed by ELISA method. Chronic administration of Δ9-THC decreased the expression of rhoA while acute treatment has no meaningful effect on it. Administration of Δ9-THC did not affect expression of rho-kinase on both chronic and acute treatment. Administration of Δ9-THC increased rho-kinase activity on both chronic and acute treatment, however, chronic treatment decreased its activity with respect to acute treatment. This study showed that chronic Δ9-THC treatment down-regulated rhoA expression and did not change the expression level of rho-kinase which is downstream effector of rhoA. However, it elevated the rho-kinase activity. Δ9-THC induced down-regulation of rhoA may cause elevation of cypin expression and may have benefit on cypin related diseases. Furthermore, use of rho-kinase inhibitors and Δ9-THC together can be useful on rho-kinase related diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29158718
http://www.sciencedirect.com/science/article/pii/S1319016417301081?via%3Dihub