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Remyelination following myelin/oligodendrocyte injury in the central nervous system (CNS) is dependent on oligodendrocyte progenitor cells (OPCs) migrating into lesion sites, differentiating into myelinating oligodendrocytes (OLs), and ensheathing axons. Experimental models indicate that robust OPC-dependent remyelination can occur in the CNS; in contrast, histologic and imaging studies of lesions in the human disease multiple sclerosis (MS) indicate the variable extent of this response, which is particularly limited in more chronic MS lesions. Immune-mediated mechanisms can contribute either positively or negatively to the presence and functional responses of OPCs. This review addresses i) the molecular signature and functional properties of OPCs in the adult human brain; ii) the status (presence and function) of OPCs in MS lesions; iii) experimental models and in vitro data highlighting the contribution of adaptive and innate immune constituents to OPC injury and remyelination; and iv) effects of MS-directed immunotherapies on OPCs, either directly or indirectly via effects on specific immune constituents. Unlabelled Image • A review of the molecular and functional properties of OPCs in the human adult brain. • Review of the evidence of the existence, identification and role of OPCs in multiple sclerosis lesions. • Detailing the effect of the adaptive and innate immune systems on OPC injury and OPC-mediated remyelination. • Understanding the direct or indirect effects of multiple sclerosis therapies on OPCs. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described neuroinflammatory demyelinating disease. To better understand the clinical spectrum, risk factors and outcomes in MOGAD. Retrospective cohort study including all subjects harboring anti-MOG antibodies identified in major academic hospitals across the province of Quebec. We identified 45 MOGAD cases. The minimal estimated point-prevalence was 0.52/100 000 in Quebec. Median age at presentation was 32 years (range 1–71) with equal sex ratio. Most frequent ethnic groups were Caucasians and Asians. The most frequent clinical manifestations at onset were optic neuritis (ON), affecting 56% of adults, and acute disseminated encephalomyelitis (ADEM), affecting 33% of children. First MRI was abnormal in 84% of cases. Most CSF samples showed pleocytosis without oligoclonal bands. Two brain biopsies revealed lipid-laden macrophages and reactive astrocytes. Despite steroids, only 38% had fully recovered at 4 weeks after onset. Half of pediatric and two thirds of adult-onset MOGAD subjects experienced relapses. At last follow-up, 69% showed residual deficits, which were moderate to severe in 17% of adults. MOGAD has heterogeneous disease course, and it is not a benign disease for a substantial proportion of adults. Best disease-modifying therapies remain to be determined. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To review the direct and indirect effects on the central nervous system (CNS) of systemically administered immuno-modulatory therapies in use or under evaluation for the relapsing forms of multiple sclerosis (MS). Methods: We summarize data published by our own lab and by others that delineate the effects of such therapies on in vitro neural cell cultures and in animal model-based systems. Results: The long-approved therapies, interferon β (IFNβ) and glatiramer acetate (GA), do not readily access the CNS. These agents can still indirectly have an effect on disease-related immune regulatory and effector functions within the CNS by modulating the properties of systemic immune cells that migrate to this compartment. Such immune cells could interact with perivascular and innate immune cells that are involved in immune regulation and with cells that are either targets of the disease process (oligodendrocytes, neurons) and/or are involved with repair (progenitor cells). Newer agents reported to favorably impact on relapse frequency in MS include the sphingosine-1-phosphate agonist, fingolimod, and the lipophilic statin, simvastatin. Both agents access the CNS and thus represent examples of agents that could directly impact on disease-relevant injury and repair process within the CNS. Conclusions: The observations reviewed in this report regarding indirect and direct effects of immuno-modulatory agents on the CNS indicate the need to understand and monitor the neurobiologic effects of such therapies. [Copyright &y& Elsevier]

A fundamental problem in oncology is that anticancer chemotherapeutics kill both cancer and healthy cells in the surrounding tissues. Resveratrol is a natural antioxidant with intriguing and opposing biological properties: it reduces viability of some cancer cells but not of non-transformed ones (in equimolar concentrations). Therefore, we examined resveratrol in human non-transformed primary astrocytes and astrocytoma. Resveratrol reduced reactive oxygen species in astrocytes, but not in astrocytoma. Such cell-type dependent response is particularly evident with analyses at the single cell level showing clear population difference in high and low glutathione levels. Due to resveratrol's poor aqueous solubility that limits its use in clinics, we incorporated it into stimulus-responsive micelles assembled from miktoarm polymers. This could be an attractive chemotherapeutic delivery strategy in nano-oncology. As a proof of principle, we show that these formulations containing resveratrol markedly decrease astrocytoma viability, particularly in combination with temozolomide, a first line chemotherapeutic for astrocytoma. Astrocytes and astrocytoma show disparity in response to resveratrol: intracellular GSH levels are increased in human primary astrocytes, while astrocytoma cells show increase in ROS and depletion of GSH. Incorporation of resveratrol in miktoarm star-based formulations, and in combination therapy with temozolomide, synergistically reduces astrocytoma cell viability. [Display omitted] • Resveratrol reduces the abundance of ROS in astrocytes but not in astrocytoma. • Cells with low or high glutathione content respond differently to resveratrol. • Miktoarm micelles are a suitable vehicle for resveratrol and other natural compounds. • Combination treatment with resveratrol effectively reduces astrocytoma viability. • Resveratrol-loaded miktoarm micelles enhance reduction in viable astrocytoma. [ABSTRACT FROM AUTHOR]

The Coronavirus disease-19 (COVID-19) pandemic continues to expand across the world. This pandemic has had a significant impact on patients with chronic diseases. Among patients with demyelinating diseases of the central nervous system (CNS), such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD), concerns remain about the potential impact of COVID-19 on these patients given their treatment with immunosuppressive or immunomodulatory therapies. In this study, we review the existing literature investigating the impact of disease-modifying therapies(DMT) on COVID-19 risks in this group of patients. For this systematic review, we searched PubMed from January 1, 2020, to December 3, 2020. The following keywords were used: "COVID-19" AND "Multiple Sclerosis" OR "Neuromyelitis Optica." Articles evaluating COVID-19 in patients with demyelinating diseases of CNS were included. This study evaluates the different aspects of the DMTs in these patients during the COVID-19 era. A total of 262 articles were found. After eliminating duplicates and unrelated research papers, a total of 84 articles met the final inclusion criteria in our study. Overall, the experiences of 2493 MS patients and 37 NMOSD patients with COVID-19 were included in this review. Among them, 46(1.8%) MS patients died(the global death-to-case ratio of Covid-19 was reported about 2.1%). Among DMTs, Rituximab had the highest mortality rate (4%). Despite controversies, especially concerning anti-CD20 monoclonal antibody therapies, a relation between DMT-use and COVID-19 disease- course was not found in many studies. This observation reinforces the recommendation of not stopping current DMTs. Other variables such as age, higher expanded disability status scale (EDSS) scores, cardiac comorbidities, and obesity were independent risk factors for severe COVID-19. Despite the risks of infection, most patients were willing to continue their DMT during the pandemic because of more significant concern about the risk of relapse or worsening MS symptoms. After the infection, an immune response's attenuation was seen in the patients on Fingolimod and anti-CD20 monoclonal antibodies. This may be a critical finding in future vaccinations. [ABSTRACT FROM AUTHOR]

Abstract: Myelin is critical in maintaining electrical impulse conduction in the central nervous system. The oligodendrocyte is the cell type responsible for myelin production within this compartment. The mutual supply of trophic support between oligodendrocytes and the underlying axons may indicate why demyelinated axons undergo degeneration more readily; the latter contributes to the neural decline in multiple sclerosis (MS). Myelin repair, termed remyelination, occurs in acute inflammatory lesions in MS and is associated with functional recovery and clinical remittances. Animal models have demonstrated that remyelination is mediated by oligodendrocyte progenitor cells (OPCs) which have responded to chemotactic cues, migrated into the lesion, proliferated, differentiated into mature oligodendrocytes, and ensheathed demyelinated axons. The limited remyelination observed in more chronic MS lesions may reflect intrinsic properties of neural cells or extrinsic deterrents. Therapeutic strategies currently under development include transplantation of exogenous OPCs and promotion of remyelination by endogenous OPCs. All currently approved MS therapies are aimed at dampening the immune response and are not directly targeting neural processes. [Copyright &y& Elsevier]

Abstract: Human self-reactive T cells are potentially involved in many autoimmune diseases. Although ex vivo detection of self-reactive T cells is possible, exhaustive functional characterization of these cells is impeded by their low frequency. In vitro expansion of antigen (Ag) specific T cells is typically achieved by using autologous (fresh or frozen) irradiated peripheral blood mononuclear cells (PBMCs), EBV-immortalized B cells or dendritic cells in the presence of Ag. These approaches require a large blood volume. We explored a method successfully applied for tumor specific T cells using in vitro expanded autologous B cells. PBMCs were stimulated with irradiated CD40L-expressing fibroblasts and IL-4, resulting in an enriched population of B cell that expressed high levels of MHC and co-stimulatory molecules, essential hallmarks of antigen presenting cells (APCs). Expanded B cells were loaded with Ag, irradiated and then used as APCs to stimulate T cells. The specificity of T cell lines was assessed by comparing their proliferation and IFN-γ secretion when cultured with antigen-loaded B cells vs. unloaded B cells. T cell lines exhibiting antigen-specific proliferation and/or IFN-γ secretion were expanded. Using this method, MBP and MOG specific CD4+ and CD8+ T cell lines were obtained from multiple donors in comparable numbers to those obtained using the traditional approach (i.e. fresh PBMCs as APCs) and were kept in culture for many weeks. We have shown that myelin specific CD4+ and CD8+ T cells can be expanded from a relatively small volume of blood (50–100 ml) from multiple donors using expanded B cells as APCs. [Copyright &y& Elsevier]

Examines the involvement of receptor-mediated apoptosis in the response of the nervous system to tissue injury. Role of tumor necrosis in mediating cytotoxicity; Implications of nerve growth factor on cell survival; Promotion of neural-immune interactions.