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      Multiple Sclerosis: Immunopathology and Treatment Update

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          Abstract

          The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS.

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Mehrdad Matloubian, Charles G Lo, Guy Cinamon … (2004)
          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Multiple sclerosis--the plaque and its pathogenesis.

            Elliot M. Frohman, Michael K Racke, Cedric Raine (2006)
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              Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.

              Jeffrey A Cohen, Alasdair J Coles, Douglas L Arnold … (2012)
              The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. Genzyme (Sanofi) and Bayer Schering Pharma. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Evanthia Bernitsas: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Brain Sci
                Journal ID (iso-abbrev): Brain Sci
                Journal ID (publisher-id): brainsci
                Title: Brain Sciences
                Publisher: MDPI
                ISSN (Electronic): 2076-3425
                Publication date (Electronic): 07 July 2017
                Publication date Collection: July 2017
                Volume: 7
                Issue: 7
                Electronic Location Identifier: 78
                Affiliations
                [1 ]Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne VIC 3030, Australia; narges.dargahi@ 123456live.vu.edu.au (N.D.); Maximilian.deCourten@ 123456vu.edu.au (M.d.C.)
                [2 ]Medical Department, Novartis (Hellas) SACI, Metamorphosis, Athens 14452, Greece; maria.katsara@ 123456novartis.com
                [3 ]Department of Chemistry, University of Patras, Rio, Patras 26500, Greece; ttselios@ 123456upatras.gr
                [4 ]Vianex S.A., Metamorphosis, Attikis, Athens 14451, Greece; AndroutsouM@ 123456vianex.gr
                [5 ]ELDrug S.A., Patras Science Park, Platani, Patras 26504, Greece; imats1953@ 123456gmail.com
                Author notes
                [* ]Correspondence: vasso.apostolopoulos@ 123456vu.edu.au ; Tel.: +61-3-9919-2025
                Author information
                https://orcid.org/0000-0001-9997-9359
                https://orcid.org/0000-0001-6788-2771
                Article
                Publisher ID: brainsci-07-00078
                DOI: 10.3390/brainsci7070078
                PMC ID: 5532591
                PubMed ID: 28686222
                SO-VID: 9c5e6f5c-0bb2-4290-acc3-3cdb25106c64
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 25 June 2017
                Date accepted : 03 July 2017
                Categories
                Subject: Review

                Keywords: multiple sclerosis,immunotherapy,drug delivery,vaccine
                Data availability:
                Keywords: multiple sclerosis, immunotherapy, drug delivery, vaccine

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