Based on the known and emerging biology of autoimmune diseases and COVID‐19, it was hypothesised that whilst B‐cell depletion should not necessarily expose people to severe SARS‐CoV‐2‐related issues, ...it may inhibit or blunt the protective immunity following infection and vaccination. This is supported clinically, as the majority of SARS‐CoV‐2 infected, CD20‐depleted people with autoimmunity, have recovered. However, in CD‐20 treated people until naïve B‐cells repopulate, based on B‐cell repopulation‐kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose‐interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS‐CoV‐29, if and when an effective vaccine is available.
Summary
Although most autoimmune diseases are considered to be CD4 T cell‐ or antibody‐mediated, many respond to CD20‐depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off‐label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID‐19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID‐19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS‐CoV‐2‐related issues, it may inhibit protective immunity following infection and vaccination. As such, drug‐induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS‐CoV‐2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS‐CoV‐2‐infected, CD20‐depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS‐CoV‐29, if and when an effective vaccine is available.
Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels have been proposed to act as metabotropic and ionotropic receptors, respectively, for two classes of endogenous ...polyunsaturated fatty acid amides, the acylethanolamides and the acyldopamides. Furthermore, we and others have shown that functional crosstalk occurs between these two receptors when they are expressed in the same cell. Although demonstrated in sensory neurons of the dorsal root ganglia, spinal cord and myenteric neurons, co-expression of cannabinoid type 1 and transient receptor potential vanilloid type 1 has not yet been studied in the brain. In the present study, we addressed this issue by using commercially available specific antibodies whose specificity was confirmed by data obtained with brains from cannabinoid type 1
−/− and transient receptor potential vanilloid type 1
−/− mice. Double cannabinoid type 1/transient receptor potential vanilloid type 1 immunofluorescence and single cannabinoid type 1 or transient receptor potential vanilloid type 1 avidin–biotin complex immunohistochemistry techniques were performed and both methods used point to the same results. Cannabinoid type 1/transient receptor potential vanilloid type 1 expression was observed in the hippocampus, basal ganglia, thalamus, hypothalamus, cerebral peduncle, pontine nuclei, periaqueductal gray matter, cerebellar cortex and dentate cerebellar nucleus. In particular, in the hippocampus, cannabinoid type 1/transient receptor potential vanilloid type 1 expression was detected on cell bodies of many pyramidal neurons throughout the CA1–CA3 subfields and in the molecular layer of dentate gyrus. In the cerebellar cortex, expression of cannabinoid type 1/transient receptor potential vanilloid type 1 receptors was found surrounding soma and axons of the vast majority of Purkinje cell bodies, whose cytoplasm was found unstained for both receptors. Cannabinoid type 1 and transient receptor potential vanilloid type 1 immunoreactivity was also detected in: a) the globus pallidus and substantia nigra, in which some intensely transient receptor potential vanilloid type 1 immunopositive cell bodies were found in dense and fine cannabinoid type 1/transient receptor potential vanilloid type 1 positive and cannabinoid type 1 positive nerve fiber meshworks, respectively; b) the cytoplasm of thalamic and hypothalamic neurons; and c) some neurons of the ventral periaqueductal gray. These data support the hypothesis of a functional relationship between the two receptor types in the CNS.
Background and Purpose:
There is increasing evidence to suggest that cannabis can ameliorate muscle‐spasticity in multiple sclerosis, as was objectively shown in experimental autoimmune ...encephalomyelitis models. The purpose of this study was to investigate further the involvement of CB
1
and CB
2
cannabinoid receptors in the control of experimental spasticity.
Experimental approach:
Spasticity was induced in wildtype and CB
1
‐deficient mice following the development of relapsing, experimental autoimmune encephalomyelitis. Spastic‐hindlimb stiffness was measured by the resistance to flexion against a strain gauge following the administration of CB
1
and CB
2
agonists.
Key Results:
As previously suggested, some CB
2
‐selective agonists (RWJ400065) could inhibit spasticity. Importantly, however, the anti‐spastic activity of RWJ400065 and the therapeutic effect of non‐selective CB
1
/CB
2
agonists (
R
(+)WIN55,212–2 and CP55, 940) was lost in spastic, CB
1
‐deficit mice.
Conclusions and Implications:
The CB
1
receptor controls spasticity and cross‐reactivity to this receptor appears to account for the therapeutic action of some CB
2
agonists. As cannabinoid‐induced psychoactivity is also mediated by the CB
1
receptor, it will be difficult to truly dissociate the therapeutic effects from the well‐known, adverse effects of cannabinoids when using cannabis as a medicine. The lack of knowledge on the true diversity of the cannabinoid system coupled with the lack of total specificity of current cannabinoid reagents makes interpretation of
in vivo
results difficult, if using a purely pharmacological approach. Gene knockout technology provides an important tool in target validation and indicates that the CB
1
receptor is the main cannabinoid target for an anti‐spastic effect.
British Journal of Pharmacology
(2007)
150
, 519–525. doi:
10.1038/sj.bjp.0707003
Clinical trials are probably the most informative experiments to help an understanding of multiple sclerosis (MS) biology. Recent successes with CD20‐depleting antibodies have focused attention ...towards B cell subsets as important mediators in MS. The trial of tabalumab (NTC00882999), which inhibits B cell activation factor (BAFF), is reported and reviewed and this trial is contrasted with the trial on the inhibition of a proliferation‐inducing ligand (APRIL) and BAFF using atacicept (NCT00642902). Both tabalumab and atacicept induce depletion of mature B cells and inhibit antibody formation, but they fail to deplete memory B cells and do not inhibit relapsing MS. Atacicept is reported to augment memory B cell responses and may precipitate relapse, suggesting the importance of APRIL. However, BAFF inhibition can enhance peripheral blood memory B cell responses, which was not associated with augmented relapse. Although other interpretations are possible, these data further support the hypothesis that memory B cells may be of central importance in relapsing MS, as they are the major CD20+ B cell subset expressing APRIL receptors. They also suggest that quantitative and/or qualitative differences in B cell responses or other factors, such as an immune‐regulatory effect associated with APRIL, may be important in determining whether MS reactivates following neutralization of peripheral B cell maturation and survival factors.
The cannabis plant (Cannabis sativa) has been known by many names but the question remains ‘Can we call it medicine?’ There has been renewed interest in the value of cannabis for the control of ...neuroinflammatory conditions such as multiple sclerosis, where it has been shown to have some effect on spasticity and pain both experimentally and in clinical trials in humans. However, in addition to symptom control potential, the question remains whether cannabinoids can modify the neuroinflammatory element which drives relapsing neurological attacks and the accumulation of progressive disability. In experimental studies it has been recently shown that synthetic cannabinoids can affect the immune response both indirectly via CB1 receptor‐mediated signalling nerve centres controlling the systemic release of immunosuppressive molecules and directly by CB2 receptor‐mediated inhibition of lymphocyte and macrophage/microglial cell function. However, these immunosuppressive possibilities that would limit the frequency of relapsing attacks will probably not be realized clinically, following use of medical cannabis, due to dose constraints. However, cannabinoids may still affect the glial response within the damaged central nervous system, which facilitate the slow, neurodegenerative processes that account for progressive neurodegeneration, and therefore may have utility in addition to value of cannabis‐related drugs for symptom control.
British Journal of Pharmacology (2007) 152, 649–654; doi:10.1038/sj.bjp.0707458; published online 24 September 2007
Occlusion or blockage of silicone shunts utilized in the treatment of hydrocephalus is a major challenge that is currently addressed by multiple shunt replacements. Shunt occlusion is caused by the ...adhesion and proliferation of reactive cells, such as glial and vascular cells, into the lumen of the catheter and on valve components. This in vitro study describes how the adhesive behavior of four human cell types on poly(dimethylsiloxane) (PDMS) surfaces can be suppressed by functionalization with trypsin, a proteolytic enzyme. The covalently conjugated trypsin retained its proteolytic activity and acted in a dose-dependent manner. Trypsin-modified PDMS surfaces supported significantly lower adhesion of normal human astrocytes, human microglia, human dermal fibroblasts, and human umbilical vein endothelial cells compared to unmodified PDMS surfaces (p < 0.0001). Immunofluorescence imaging of cellular fibronectin and quantitative adsorption experiments with serum components indicated that the PDMS surfaces immobilized with trypsin inhibited surface remodeling by all cell types and resisted protein adsorption. The impact of this work lies in the recognition that the well-known proteolytic characteristics of trypsin can be harnessed by covalent surface immobilization to suppress cell adhesion and protein adsorption.
Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental ...allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excito toxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.
The pathological correlate of clinical disability and progression in multiple sclerosis is neuronal and axonal loss; however, the underlying mechanisms are unknown. Abnormal phosphorylation of tau is ...a common feature of some neurodegenerative disorders, such as Alzheimer's disease. We investigated the presence of tau hyperphosphorylation and its relationship with neuronal and axonal loss in chronic experimental autoimmune encephalomyelitis (CEAE) and in brain samples from patients with secondary progressive multiple sclerosis. We report the novel finding of abnormal tau phosphorylation in CEAE. We further show that accumulation of insoluble tau is associated with both neuronal and axonal loss that correlates with progression from relapsing–remitting to chronic stages of EAE. Significantly, analysis of secondary progressive multiple sclerosis brain tissue also revealed abnormally phosphorylated tau and the formation of insoluble tau. Together, these observations provide the first evidence implicating abnormal tau in the neurodegenerative phase of tissue injury in experimental and human demyelinating disease.
Background:
It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and ...multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects.
Objective:
We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects.
Methods:
Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge.
Results:
Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184.
Conclusions:
This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use.
ABSTRACT
Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with ...nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2‐arachidonoyl glycerol (2‐AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non‐spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re‐uptake and hydrolysis—probably through the enhancement of endogenous levels of AEA, and, possibly, 2‐arachidonoyl glycerol—significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.
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