Radu Tanasescu

Cannabinoids and the immune system: an overview.

Cannabinoids can influence the immune network. Data on the impact of exogenous cannabinoid ligands on immune function serve not only to understand how the endocannabinoid system modulates immune phenomena associated with infection or inflammation, but also to identify therapeutic targets for immune diseases. Cannabinoids can modulate immune reactions in the periphery but also in the brain, influence T cell subset balance and cytokine expression and play a role in the balance between neuroinflammation and neurodegeneration. Immune cells can synthesize endocannabinoids and also be influenced by cannabinoid analogues. Cannabinoid receptors show different expression on immune cells depending on activation status and stimuli. The complexity of relation between cannabinoid ligands of various classes and cannabinoid receptors brought the need to refine the simple conceptual frame of agonist-antagonists and offered potential implications for understanding interactions in pathological conditions. The immune influence of cannabinoid ligands is not fully elucidated. However, aspects of their immunomodulatory effects provide the basis for a context-dependent targeted therapeutic approach, thus leading to the possibility for the use of cannabinoids in the treatment of inflammatory disease.

Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis

Objectives: To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity. Methods: In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety. Results: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time. Conclusions: MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found. Classification of evidence: This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS.

Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios

Objective There are inconsistent data on mortality in people with multiple sclerosis (MS). We performed a meta-analysis of all-cause, cause-specific and gender-specific crude mortality rates (CMRs), and standardised mortality ratios (SMRs) in MS, and estimated the rate of change of CMR and SMR over the past 50 years. Methods Medline, Embase and the Cochrane Library were searched. Keywords: ‘Multiple Sclerosis’ and (‘standardised mortality’ or ‘standardized mortality’). Inclusion criteria: availability of data on the number of deaths; mean or median patient follow-up or reports of SMRs; being a longitudinal study. 12 studies were included covering the period 1949–2012 (27 423 patients; 6628 deaths; 437 832 person-years follow-up). CMR was calculated. SMRs were extracted. CMRs and natural logarithm of SMRs were pooled by the method of the inverse of the variance. Meta-regression models were used to investigate the secular trends. Results Pooled CMR was 9.78/1000 person-years (95% CI 6.81 to 14.02). Pooled all-cause SMR was 2.80 (95% CI 2.74 to 2.87). All-cause SMR was 2.56 (95% CI 2.47 to 2.66) in males and 3.06 (95% CI 2.97 to 3.17) in females. SMR due to cancer was 0.89 (95% CI 0.83 to 0.97). SMRs due to cardiovascular diseases, suicide, infection and respiratory diseases were 1.29 (95% CI 1.20 to 1.38), 2.13 (95% CI 1.80 to 2.51) and 2.91 (95% CI 2.60 to 3.26). There was no trend in CMRs, all-cause, and gender-specific SMRs. Conclusions The excess mortality in MS relative to the general population has not changed over the past 50 years. Female patients with MS have higher survival disadvantage compared to that of males. Death due to cardiovascular diseases, suicide and infection is higher in patients with MS compared to the general population.

Acute myeloid leukaemia induced by mitoxantrone in a multiple sclerosis patient

Sirs: Mitoxantrone (MITO) is an anthracenedione antineoplastic agent utilised in the treatment of the most active stages of multiple sclerosis (MS) [2, 8, 10]. Usually MITO is administrated as a singleagent disease-modifying therapy, and MS patients should not receive a cumulative total dosage of MITO exceeding 140 mg/m2. The adverse effects of MITO are cardio toxicity and therapy-related acute myeloid leukaemia (trAML). We report a case in France of a MS patient treated by MITO and cyclophosphamide who developed trAML.

Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells

To investigate the regulation of cannabinoid receptors CB1 and CB2 on immune cells by pro‐inflammatory cytokines and its potential relevance to the inflammatory neurological disease, multiple sclerosis (MS).

The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis

Background The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS. Objective To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients. Methods Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association. Results 43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF. Conclusions This systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.

Advances in the treatment of relapsing-remitting multiple sclerosis.

This article reviews and discusses the approved and emerging therapies for multiple sclerosis (MS). MS is a chronic and disabling immune-mediated disease of the central nervous system (CNS) that affects mainly young adults. MS imposes a huge economic burden on healthcare systems and the society. Although the last 20 years have brought a continuous expansion in therapeutic options, there are still unmet needs in MS management. Available MS drugs have varying degrees of efficacy in reducing relapse risk. The long-term term effects of these treatments are incompletely known. New therapies, along with variations of currently available treatments, may prove more effective and tolerable than the available drugs. Treatments for MS differ with respect to the mode of administration, tolerability and likelihood of treatment adherence, side effects, and risk of major toxicity. The armamentarium of approved disease-modifying therapies in MS and those in development include: (1) the first approved, moderately effective, injectable interferon-β and glatiramer acetate; (2) oral drugs (fingolimod, laquinimod, teriflunomide, dimethyl fumarate); (3) monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab); and (4) immunosuppressive agents (e.g. mitoxantrone). The place of each drug in the therapeutic algorithm is dependent on its specific risk-benefit profile. Patients′ clinical and paraclinical phenotypes and biomarker profile may help to elucidate disease subtypes and response to therapy in the future, thus allowing treatment individualization.

Innate immune regulation of autoimmunity in multiple sclerosis: Focus on the role of Toll-like receptor 2

Innate immunity relies on a set of germline-encoded receptors including Toll-like receptors (TLRs) that enable the host to discriminate between self and non-self. Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS). Infections are thought to play an important role in disease susceptibility. The role of innate immunity in MS has been recently appreciated. TLR2, a member of the TLR family, forms heterodimers with either TLR1 or TLR6 and detects a wide range of microbial as well as self-derived molecular structures. It may thus be important both in fighting infection and in activating autoimmunity. In this review, we discuss innate regulation of autoimmunity in MS with a focus on the role of TLR2 signaling.

Reciprocal Regulation of Substance P and IL-12/IL-23 and the Associated Cytokines, IFNγ/IL-17: A Perspective on the Relevance of This Interaction to Multiple Sclerosis

The neuropeptide substance P (SP) exhibits cytokine-like properties and exerts different effects in autoimmune inflammation. Various immune cells express SP and its neurokinin-1 receptor (NK1R) isoforms. A role for SP has been demonstrated in a number of autoimmune conditions, including multiple sclerosis (MS). In this work, we studied the role of SP and NK1R in human immune cells with a focus on their relationship with IL-12/IL-23 family cytokines and the associated IFN-γ/IL-17. AIMS: (1) To determine the role of SP mediated effects on induction of various inflammatory cytokines in peripheral blood mononuclear cells (PBMC); (2) to investigate the expression of SP and its receptor in T cells and the effects of stimulation with IL-12 and IL-23. Quantitative real-time PCR, flow cytometry, ELISA, promoter studies on PBMC and primary T cells from healthy volunteers, and Jurkat cell line. Treatment with SP significantly increased the expression of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA in human PBMC. Expression of NK1R and SP in T cells was upregulated by IL-23 but a trend was observed with IL-12. The IL-23 effect likely involves IL-17 production that additionally mediates IL-23 effects. Mutual interactions exist with SP enhancing the cytokines IL-23 and IL-12, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. These findings suggest a proinflammatory role for SP in autoimmune inflammation. We propose a model whereby immunocyte derived SP stimulates Th1 and Th17 autoreactive cells migrating to the central nervous system (CNS), enhances their crossing the blood brain barrier and perpetuates inflammation in the CNS by being released from damaged nerves and activating both resident glia and infiltrating immune cells. SP may be a therapeutic target in MS.

Coordinate Based Meta-Analysis of Functional Neuroimaging Data; False Discovery Control and Diagnostics

Coordinate based meta-analysis (CBMA) is widely used to find regions of consistent activation across fMRI studies that have been selected for their functional relevance to a given hypothesis. Only reported coordinates (foci), and a model of their spatial uncertainty, are used in the analysis. Results are clusters of foci where multiple studies have reported in the same spatial region, indicating functional relevance. There are several published methods that perform the analysis in a voxel-wise manner, resulting in around 105 statistical tests, and considerable emphasis placed on controlling the risk of type 1 statistical error. Here we address this issue by dramatically reducing the number of tests, and by introducing a new false discovery rate control: the false cluster discovery rate (FCDR). FCDR is particularly interpretable and relevant to the results of CBMA, controlling the type 1 error by limiting the proportion of clusters that are expected under the null hypothesis. We also introduce a data diagnostic scheme to help ensure quality of the analysis, and demonstrate its use in the example studies. We show that we control the false clusters better than the widely used ALE method by performing numerical experiments, and that our clustering scheme results in more complete reporting of structures relevant to the functional task.