Category Archives: Autoimmune Disease

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

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“Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis…

This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases.

Cannabidiol (CBD) is a major non-psychoactive cannabinoid component of marijuana.

Together, these studies not only demonstrate that CBD can protect the host from acute liver injury but also provide evidence for the first time that MDSCs may play a critical role in protecting the liver from acute inflammation.

Non-psychoactive cannabinoids such as CBD possess great therapeutic potential in treating various inflammatory liver diseases, including autoimmune hepatitis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069975/

Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis.

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“Our aim was to evaluate the roles of the cannabinoid pathway in the induction and propagation of systemic sclerosis (SSc) in a mouse model…

Experiments performed in CB2-deficient mice confirmed the influence of CB2 in the development of systemic fibrosis and autoimmunity. Therefore, we demonstrate that the CB2 receptor is a potential target for the treatment of SSc because it controls both skin fibroblast proliferation and the autoimmune reaction.

In this report, we demonstrate for the first time the highly protective role of cannabinoid agonists in SSc. Because these agonists are available and well-tolerated under clinical conditions, our data offer a new therapeutic opportunity in this life-threatening disease.

In conclusion, modulation of the endocannabinoid system is a novel approach for the treatment of various inflammatory diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893662/

Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists

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“The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance.

Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential.

In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive.

The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision.

We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered.

Therapeutically relevant cannabinoid receptor ligands include tetra-hydrocannabinol itself, its synthetic forms, and its closely related compounds.

As a final point, the application of CB1 antagonists may be immunostimulative…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804300/

Cannabinoid Receptor Type 1- and 2-mediated Increase in Cyclic AMP Inhibits T Cell Receptor-triggered Signaling

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FIGURE 1.

“The aim of this study was to characterize inhibitory mechanisms on T cell receptor signaling mediated by the cannabinoid receptors CB1 and CB2. Both receptors are coupled to G(i/o) proteins, which are associated with inhibition of cyclic AMP formation…

These findings help to better understand the immunosuppressive effects of cannabinoids and explain the beneficial effects of these drugs in the treatment of T cell-mediated autoimmune disorders like multiple sclerosis.

To sum up, our results help to explain immunosuppressive effect of cannabinoid drugs, which may be important for the pharmacological evaluation of these drugs, e.g. with respect to their use in neuroinflammatory diseases and T cell-mediated autoimmune disorders like multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790974/#!po=45.6522

Targeting the CB2 receptor for immune modulation.

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“Early work on the biology of the components of Cannabis sativa showed evidence for a potential influence on immune regulation.

With the discovery of a peripheral cannabinoid receptor associated with immune cells, many laboratories have sought to link the immunoregulatory activities of cannabinoid compounds with this receptor, hoping that such compounds would lack the psychoactive effects of marijuana and other nonspecific cannabinoid agonists.

In this report, the authors investigate the role of the cannabinoid CB2 receptor in immune regulation, with particular emphasis on compounds shown to regulate immune cell recruitment.

The authors conclude by using the immune cell recruitment model to rationalise cannabinoidCB2 receptor-specific effects in modulating immune disease, particularly the increasing evidence for its role in experimental autoimmuneencephalomyelitis and in influencing bone density.”

http://www.ncbi.nlm.nih.gov/pubmed/16981823

Updating the chemistry and biology of cannabinoid CB2 receptor-specific inverse agonists.

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“The cannabinoid CB(2) receptor continues to be an intriguing target for the potential therapeutic benefit of cannabinoids. Because this receptor is significantly found outside the brain, compounds specific for the CB(2) receptor may be free of the side effects that have plagued cannabinoid CB(1) receptor-based therapeutics.

In this review, we will discuss a class of compounds which modulate the constitutive activity of the cannabinoid CB(2) receptor, the inverse agonists. We will discuss recent chemical advances that provide new compounds to investigate the biology based on this pharmacology. We will then discuss new biology associated with the cannabinoid CB(2) receptor for hints of how these compounds can best be utilized in vivo.”

http://www.ncbi.nlm.nih.gov/pubmed/20370714

Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists

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Figure 2

“Evidence has emerged suggesting a role for the cannabinoid CB2 receptor in immune cell motility. This provides a rationale for a novel and generalized immunoregulatory role for cannabinoid CB2 receptor-specific compounds…

An ability to control the migration of inflammatory cells to the site of insult is a powerful strategy for the development of immunomodulators. Our work on triaryl bis-sulphones suggest that the cannabinoid CB2 receptor-specific inverse agonists may serve as such immune modulators…

Further studies, using these and other CB2 receptor-specific compounds, will be required to resolve the complex pharmacology of cannabinoids and the cannabinoid CB2 receptor, and to determine the most effective pharmacology to exploit this therapeutic target.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219522/

Cannabinoid Modulation of Neuroinflammatory Disorders

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Table 1.

“Cannabis sativa is a herb belonging to the Cannabaceae family, characterized by palmate leaves and numerous fibers. Its first record as a medicine dates back to 5000 years ago and it was found in China, where cannabis was used for a myriad of purposes and diseases, including malaria, neuropathic pain, nausea, sexual dysfunction and constipation.

The use of cannabis spread from Central Asia and deeply influenced Indian folk medicine. However, sedative and psychotropic effects of cannabis turned it into a recreational drug. This fact resulted in discrimination against the consumption of the cannabis plant and its derivatives, which delayed the scientific findings in this field…

In recent years, a growing interest has been dedicated to the study of the endocannabinoid system. The isolation of Cannabis sativa main psychotropic compound, Δ(9)-tetrahydrocannabinol (THC), has led to the discovery of an atypical neurotransmission system that modulates the release of other neurotransmitters and participates in many biological processes, including the cascade of inflammatory responses.

In this context, cannabinoids have been studied for their possible therapeutic properties in neuroinflammatory diseases. In this review, historic and biochemical aspects of cannabinoids are discussed, as well as their function as modulators of inflammatory processes and therapeutic perspectives for neurodegenerative disorders, particularly, multiple sclerosis.

Cannabinoid compounds may be extracted from the plant (phytocannabinoids) or be artificially obtained (synthetic cannabinoids)…

To date, it is still impossible to prove or rule out all benefits of cannabis described empirically by ancient herbal practitioners. For now, science aims to understand how cannabinoid compounds are associated with neuroinflammation and how cannabis-based medicine can help millions of patients worldwide.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386505/

Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation.

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<br /> FIGURE 1.<br />

“Cannabinoids are compounds derived from the Cannabis sativa (marijuana) plant, as well as produced endogenously in the brain and by immune cells. Cannabinoids mediate their effect through cannabinoid receptors (CB), designated CB1 and CB2, which belong to a superfamily of G-protein-coupled receptors.

CB1 receptors are expressed at high levels in CNS, where they regulate psychoactivity. CB1 receptors are also expressed on immune cells. In contrast, the CB2 receptors are primarily expressed on immune cells and do not contribute to the psychoactivity. The presence of endogenous CB-ligand systems in immune cells suggests that they may play a critical physiological role, the precise nature of which remains to be characterized.

Cannabinoids can decrease the immune response… Cannabinoids have also been widely used in the treatment of pain and inflammation.

Moreover, preliminary studies have shown the possible use of cannabinoids in the treatment of autoimmune diseases such as multiple sclerosis.

Recent studies from our lab demonstrated that Δ9-tetrahydrocannabinol (THC) can trigger apoptosis in vivo in thymocytes and splenocytes, which may account for immunosuppression.

 We demonstrate for the first time that THC and endocannabinoids such as anandamide can induce apoptosis in DCs through activation of CB1 and CB2 receptors.

These studies provide the basis for understanding the mechanism by which THC triggers immunosuppression and mediates anti-inflammatory properties.

Many studies have suggested the use of THC or related cannabinoids in the treatment of autoimmune diseases.”

http://www.jimmunol.org/content/173/4/2373.long

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents.

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“Marijuana has been used for recreational and medicinal purposes for centuries. Its medicinal use can be traced back to ancient Chinese and Egyptian civilizations…

Cannabinoids are known to interact with CB1 and CB2 receptors expressed in the nervous and immune system, respectively, and mediate a wide range of effects, including anti-inflammatory properties…

The current study suggests that targeting CB2 receptors may constitute a unique treatment modality against inflammatory diseases…

Together, this study suggests that CB2-selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1864948/