Yang Mao-Draayer

Dimethyl Fumarate Protects Neural Stem/Progenitor Cells and Neurons from Oxidative Damage through Nrf2-ERK1/2 MAPK Pathway

Multiple sclerosis (MS) is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS). Due to the progressive neurodegenerative nature of MS, developing treatments that exhibit direct neuroprotective effects are needed. Tecfidera™ (BG-12) is an oral formulation of the fumaric acid esters (FAE), containing the active metabolite dimethyl fumarate (DMF). Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanism of action in MS is not yet well understood. In this study, we reported the potential neuroprotective effects of dimethyl fumarate (DMF) on mouse and rat neural stem/progenitor cells (NPCs) and neurons. We found that DMF increased the frequency of the multipotent neurospheres and the survival of NPCs following oxidative stress with hydrogen peroxide (H2O2) treatment. In addition, utilizing the reactive oxygen species (ROS) assay, we showed that DMF reduced ROS production induced by H2O2. DMF also decreased oxidative stress-induced apoptosis. Using motor neuron survival assay, DMF significantly promoted survival of motor neurons under oxidative stress. We further analyzed the expression of oxidative stress-induced genes in the NPC cultures and showed that DMF increased the expression of transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) at both levels of RNA and protein. Furthermore, we demonstrated the involvement of Nrf2-ERK1/2 MAPK pathway in DMF-mediated neuroprotection. Finally, we utilized SuperArray gene screen technology to identify additional anti-oxidative stress genes (Gstp1, Sod2, Nqo1, Srxn1, Fth1). Our data suggests that analysis of anti-oxidative stress mechanisms may yield further insights into new targets for treatment of multiple sclerosis (MS).

Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients

Dimethyl fumarate (DMF; trade name Tecfidera) is an oral formulation of the fumaric acid ester that is Food and Drug Administration approved for treatment of relapsing-remitting multiple sclerosis. To better understand the therapeutic effects of Tecfidera and its rare side effect of progressive multifocal leukoencephalopathy, we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated and 4–6 and 18–26 mo Tecfidera-treated stable relapsing-remitting multiple sclerosis patients using multiparametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportions of both effector memory T cells and central memory T cells were reduced, whereas naive T cells increased in treated patients. T cell activation was reduced with DMF treatment, especially among effector memory T cells and effector memory RA T cells. Th subsets Th1 (CXCR3+), Th17 (CCR6+), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, whereas the anti-inflammatory Th2 subset (CCR3+) was increased after DMF treatment. A corresponding increase in IL-4 and decrease in IFN-γ and IL-17–expressing CD4+ T cells were observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment.

The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases.

Multiple sclerosis (MS) is a prototype autoimmune disease of the central nervous system (CNS). Currently, there is no drug that provides a cure for MS. To date, all immunotherapeutic drugs target relapsing remitting MS (RR-MS); it remains a daunting medical challenge in MS to develop therapy for secondary progressive MS (SP-MS). Since the approval of the non-selective sphingosine-1-phosphate (S1P) receptor modulator FTY720 (fingolimod [Gilenya®]) for RR-MS in 2010, there have been many emerging studies with various selective S1P receptor modulators in other autoimmune conditions. In this article, we will review how S1P receptor may be a promising therapeutic target for SP-MS and other autoimmune diseases such as psoriasis, polymyositis and lupus.

The gut microbiome and microbial translocation in multiple sclerosis

Individuals with multiple sclerosis (MS) have a distinct intestinal microbial community (microbiota) and increased low-grade translocation of bacteria from the intestines into the circulation. The observed change of intestinal bacteria in MS patients regulate immune functions involved in MS pathogenesis. These functions include: systemic and central nervous system (CNS) immunity (including peripheral regulatory T cell function), the blood-brain barrier (BBB) permeability and CNS-resident cell activity. This review discusses the MS intestinal microbiota implication on MS systemic- and CNS-immunopathology. We introduce the possible contributions of MS low-grade microbial translocation (LG-MT) to the development of MS, and end on a discussion on microbiota therapies for MS patients.

Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis

Dimethyl fumarate (DMF) is an effective treatment option for relapsing–remitting multiple sclerosis (MS), but its therapeutic mechanism of action has not been fully elucidated. A better understanding of its mechanism will allow for the development of assays to monitor its clinical efficacy and safety in patients, as well as guide the development of the next generation of therapies for MS. In order to build the foundation for determining its mechanism, we reviewed the manner in which DMF alters lymphocyte subsets in MS patients, its impact on clinical efficacy and safety, as well as its molecular effects in cellular and animal models. DMF decreases absolute lymphocyte counts, but does not affect all subsets uniformly. CD8+ T-cells are the most profoundly affected, but reduction also occurs in the CD4+ population, particularly within the pro-inflammatory T-helper Th1 and Th17 subsets, creating a bias toward more anti-inflammatory Th2 and regulatory subsets. Similarly, B-lymphocyte, myeloid, and natural killer populations are also shifted toward a more anti-inflammatory state. In vitro and animal models demonstrate a role for DMF within the central nervous system (CNS) in promoting neuronal survival in an Nrf2 pathway-dependent manner. However, the impact of DMF directly within the CNS of MS patients remains largely unknown.

Impact of Cytokines on Neural Stem/Progenitor Cell Fate

Neural stem/progenitor cells (NSC/NPC) can be a powerful tool for the neural repair of the damaged brain. Many of the current challenges with stem cell therapies revolve around the problem that stem cells do not survive, migrate, proliferate and differentiate as much as hoped. Understanding the interaction between NPCs and the immune system is essential for the effective use of stem cell transplantation. Cytokines play an important role in determining the inflammatory microenvironment and have also been shown to have effects on the differentiation, proliferation, migration and survival of NPCs. The effects of cytokines on neural stem cell fate is more complex than once believed; the distinction between anti-inflammatory and pro- inflammatory cytokines is not straightforward and varies based on conditions such as cytokine concentration and area of transplantation. If their role is understood, cytokines could be used to improve the efficacy of stem cell treatments and enhance neural repair. In this review, we provide a comprehensive overview of the effects of various cytokines on NPC fate. The ultimate goal of this review is to demonstrate how manipulation of the CNS microenvironment through alteration of various cytokines can enhance the capacity of NPC differentiation, proliferation, and overall neural repair.

Neurosarcoidosis in a patient treated with tumor necrosis factor alpha inhibitors.

We describe the case of a 36-year-old Caucasian man with a 9-year history of HLA-B27-positive ankylosing spondylitis, who presented with new seizures. He had a non-focal neurological exam. Blood tests showed mild leukocytosis and elevation in liver transaminases. Initial head CT showed hypodensity in the left frontal subcortical white matter. MRI of the brain showed leptomeningeal enhancement and several hyperintense lesions (Fig. 1a–c). He had been on adalimumab (Humira ) for 3 years, but this was discontinued as a repeat MRI showed progression and increased size of the lesions 1 month later. He was then treated with intravenous SoluMedrol at 1 g/day for 5 days with prednisone taper and maintained on methotrexate. CSF studies showed mild lymphocytic leukocytosis and elevated protein. EEG showed bihemispheric slowing; left worse than right. Brain biopsy showed well-formed non-caseating granulomas consistent with neurosarcoidosis (Fig. 2a–c). Leading up to this presentation, he had also been treated with etanercept (Enbrel ) for 2 years prior to adalimumab. Tumor necrosis factor alpha inhibitors (TNFAIs) include etanercept (Enbrel )—a TNFa p75 soluble receptor fusion protein; and adalimumab (Humira ) and infliximab (Remicade )—both monoclonal antibody to TNFa. Despite the efficacy of TNFAIs in many autoimmune arthropathies and refractory sarcoidosis, treatment with these agents may have a paradoxical effect, as seen in this case. Neurosarcoidosis, in the presence of multisystem organ involvement and neurologic deficits, has an incidence of approximately 1 per 100,000 and is present in 5 % of systemic sarcoidosis cases [1]. It has been found strictly confined to the CNS in approximately 0.2 per 100,000. CNS involvement usually reveals granulomatous infiltration of the meninges and parenchyma, most prominent at the base of the brain [2, 3]. The etiology of sarcoidosis remains unknown; however, it may possibly be linked to genetic susceptibility with increased Th1 immune response to environmental factors [4]. TNFa is one of the main cytokines responsible for initiation and formation of granulomas; therefore, besides cytotoxic drugs such as methotrexate, azathioprine, and cyclosporine, TNFAIs have been used in some refractory cases of sarcoidosis [5, 6]. Combination treatment with mycophenolate mofetil and infliximab was shown to be effective in treating neurosarcoidosis [7]. Considering this known pathological correlation and efficacy of TNFAIs, it is somewhat surprising and paradoxical that TNFAIs would cause granulomatosis. Tong et al. [8] summarized a total of 37 cases of sarcoidlike granuloma development after TNFAIs therapy. This phenomenon was reported in all three TNFAIs, suggesting this is a ‘‘class effect’’ [8–10]. Almost all cases are peripheral sarcoidosis of the lungs and skin [8]. There was only one case of neurosarcoidosis reported in a 41-year-old female being on infliximab and methotrexate for rheumatoid arthritis [11]. In our case, the temporal relationship between neurosarcoidosis development while being on etanercept and adalimumab, and resolution of the disease while being off the agents, is highly suggestive of causality. We did not rechallenge the patient with another TNFAI as there has been previous reports on recurrence of sarcoidlike granulomas with rechallenging [8, 12]. Y. Mao-Draayer (&) Neurology Department, University of Michigan, Ann Arbor, MI 48103, USA e-mail: maodraay@med.umich.edu

Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment

The clinical success of anti-CD20 monoclonal antibody (mAb)-mediated B cell depletion therapy has contributed to the understanding of B cells as major players in several autoimmune diseases. The first therapeutic anti-CD20 mAb, rituximab, is a murine–human chimera to which many patients develop antibodies and/or experience infusion-related reactions. A second generation of anti-CD20 mAbs has been designed to be more effective, better tolerated, and of lower immunogenicity. These include the humanized versions: ocrelizumab, obinutuzumab, and veltuzumab, and the fully human, ofatumumab. We conducted a literature search of relevant randomized clinical trials in the PubMed database and ongoing trials in Clinicaltrials.gov. Most of these trials have evaluated intravenous ocrelizumab or subcutaneous ofatumumab in rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus. Understanding how newer anti-CD20 mAbs compare with rituximab in terms of efficacy, safety, convenience, and cost is important for guiding future management of anti-CD20 mAb therapy in autoimmune diseases.

Understanding progressive multifocal leukoencephalopathy risk in multiple sclerosis patients treated with immunomodulatory therapies: A bird's eye view

The increased use of newer potent immunomodulatory therapies for multiple sclerosis (MS), including natalizumab, fingolimod, and dimethyl fumarate, has expanded the patient population at risk for developing progressive multifocal leukoencephalopathy (PML). These MS therapies shift the profile of lymphocytes within the central nervous system (CNS) leading to increased anti-inflammatory subsets and decreased immunosurveillance. Similar to MS, PML is a demyelinating disease of the CNS, but it is caused by the JC virus. The manifestation of PML requires the presence of an active, genetically rearranged form of the JC virus within CNS glial cells, coupled with the loss of appropriate JC virus-specific immune responses. The reliability of metrics used to predict risk for PML could be improved if all three components, i.e., viral genetic strain, localization, and host immune function, were taken into account. Advances in our understanding of the critical lymphocyte subpopulation changes induced by these MS therapies and ability to detect viral mutation and reactivation will facilitate efforts to develop these metrics.

Emerging approaches for validating and managing multiple sclerosis relapse

The autoimmune disease multiple sclerosis (MS) is characterized by relapses in the majority of patients. A definitive clinical diagnosis of relapse in MS can be complicated by the presence of an infection or comorbid disorder. In this mini-review, we describe efforts to develop enhanced imaging techniques and biomarker detection as future tools for relapse validation. There is emerging evidence of roles for meningeal inflammation, sex hormones, comorbid metabolic or mood disorders, and a dysregulated immune profile in the manifestation and severity of relapse. Specific subsets of immune cells likely drive the pathophysiology of relapse, and identification of a patient’s unique immunological signature of relapse may help guide future diagnosis and treatment. Finally, these studies highlight the diversity in terms of relapse presentation, immunological signature, and response in patients with MS, indicating that going forward the best approach to assessment and treatment of relapse will be multifactorial and highly personalized.