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      Immunological Aspects of Approved MS Therapeutics

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          Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.

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

          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.

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              Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.

              Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                11 July 2019
                : 10
                1Department of Neurology, Medical University of Vienna , Vienna, Austria
                2Department of Neurology, Barzilai University Medical Center , Ashkelon, Israel
                3Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer-Sheva, Israel
                4Neuroimmunology Division, Department of Neurology and Neurological Sciences, Stanford University , Stanford, CA, United States
                5Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University , Salzburg, Austria
                6Department of Neurology, Klinikum Rechts der Isar, Technische Universität , Munich, Germany
                7Department of Psychiatry, Psychotherapy, and Psychosomatics, Christian Doppler Medical Center, Paracelsus Medical University , Salzburg, Austria
                8Department of Neurology, Odense University Hospital , Odense, Denmark
                9Institute of Clinical Research, University of Southern Denmark , Odense, Denmark
                10Department of Neurology, Medical Faculty, University of Köln , Cologne, Germany
                11Institute of Neuropathology, University Medical Center , Göttingen, Germany
                12Department of Neurology, University Medical Center , Göttingen, Germany
                13Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center , Dallas, TX, United States
                14Neurology Section, VA North Texas Health Care System, Medical Service Dallas, VA Medical Center , Dallas, TX, United States
                Author notes

                Edited by: Björn Tackenberg, University of Marburg, Germany

                Reviewed by: Michael Levy, Massachusetts General Hospital and Harvard Medical School, United States; Jeannette Lechner-Scott, Hunter New England Health, Australia

                *Correspondence: Paulus S. Rommer paulus.rommer@ 123456meduniwien.ac.at

                This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology

                Copyright © 2019 Rommer, Milo, Han, Satyanarayan, Sellner, Hauer, Illes, Warnke, Laurent, Weber, Zhang and Stuve.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 0, Tables: 4, Equations: 0, References: 283, Pages: 24, Words: 22974


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