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      Should mast cells be considered therapeutic targets in multiple sclerosis?

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          Abstract

          Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

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          Multiple sclerosis

          Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing-remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers.
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            The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells

            The nature of the inflammatory response in the MS brain is poorly defined. Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8+ T-cells and CD20+ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.
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              Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.

              A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.
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                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regeneration Research
                Wolters Kluwer - Medknow (India )
                1673-5374
                1876-7958
                November 2020
                11 May 2020
                : 15
                : 11
                : 1995-2007
                Affiliations
                [1 ]Institute of Biosciences, Department of Microbiology and Immunology, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
                [2 ]Bauru School of Dentistry, Department of Surgery, Stomatology, Pathology and Radiology, University of São Paulo, Bauru, São Paulo, Brazil
                Author notes
                [* ] Correspondence to: Karen Henriette Pinke, karen.pinke@ 123456gmail.com .

                Author contributions: All authors contributed to the content of the review and approved the final manuscript.

                Author information
                http://orcid.org/0000-0001-8716-1250
                Article
                NRR-15-1995
                10.4103/1673-5374.282238
                7716037
                32394947
                a8525008-22e7-4716-ac25-6018c32af283
                Copyright: © 2020 Neural Regeneration Research

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 02 December 2019
                : 19 December 2019
                : 16 January 2020
                Categories
                Review

                central nervous system,degenerative disease,experimental autoimmune encephalomyelitis,immunity,immunomodulatory drugs,inflammatory disease,ketotifen fumarate,mast cells,multiple sclerosis,therapeutic target

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