To view this page ensure that Adobe Flash Player version 11.1.0 or greater is installed.

Review Multiple Sclerosis Selective Targeting of T and B Cell Populations by Alemtuzumab in the Treatment of Multiple Sclerosis Nikolaos C Grigoriadis AHEPA University Hospital, Thessaloniki, Greece U pstream targeting of both T and B cells is a rational therapeutic approach in multiple sclerosis (MS) in view of how both cell types and the interaction between them contribute to MS pathophysiology. This article will discuss this new way of thinking in MS: the targeting of both T and B cells, with a focus on the recently developed therapy, alemtuzumab (Lemtrada ® , Genzyme, UK). Alemtuzumab depletes T and B lymphocytes, mainly via complement-dependent cytolysis and antibody-dependent cytolysis; depletion of B cells is not an enduring effect compared with the depletion of T cells. After dosing, CD4+ and CD8+ T cells and CD19 B cells decrease initially but increase over the following 11 months. During repopulation after alemtuzumab treatment, there is a shift in the relative proportions of T cell and B cell subsets whereby proportions of regulatory T cells and memory-phenotype T cells are increased and the proportion of naïve T cells is decreased. A switch from a pro- to an anti-inflammatory phenotype and cytokine profile caused by alemtuzumab may underpin the long-lasting suppression of MS activity that has been observed in clinical trials. Alemtuzumab treatment is also associated with a consistently good safety and tolerability profile. Further, alemtuzumab appears to promote neurorehabilitation by improving measures of physical functioning, disability, measures of quality of life, and brain volume loss. Alemtuzumab therefore has the potential to reduce disease burden and improve substantially the prognosis for patients with MS. Keywords T and B cells in multiple sclerosis immunopathology Multiple sclerosis (MS), pathophysiology, immunotherapy, alemtuzumab, mechanism of action Knowledge of multiple sclerosis (MS) pathophysiology has progressed dramatically from the first description of the disease in 1868 to the understanding of immune processes in the 1990s to the present day. Genetic 1,2 and environmental 3 factors contribute to MS and cause an imbalance in immune regulatory networks comprising both T and B cells. 4–6 In MS, the balance of T cell subtypes and responses is skewed. CD4+ naïve T cells differentiate into different cell types. Disclosure: Nikolaos C Grigoriadis has received honoraria, travel support, and consultancy and lecture fees from: Biogen Idec; Novartis; TEVA; Bayer; Merck Serono, Genesis Pharma; and Genzyme, a Sanofi Company. He has also received research grants from: Biogen Idec; Novartis; TEVA; Merck Serono; and Genesis Pharma. Acknowledgements: Editorial assistance was provided by Catherine Amey at Touch Medical Media, and was supported by Touch Medical Media. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 20 August 2016 Accepted: 16 May 2017 Citation: European Neurological Review, 2017;12(2):78–83 Corresponding Author: Nikolaos C Grigoriadis, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilp Kyriakidi str, GR 54636 Thessaloniki, Central Macedonia, Greece. E: grigoria@med.auth.gr; ngrigoriadis@auth.gr Support: No funding was received in the publication of this article. 78 • The number of Th17 cells is increased. 7 • In the central nervous system (CNS), microglial cells produce pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α, and cytotoxic substances such as reactive oxygen species and reactive nitrogen species that lead to neuro-inflammation and the direct destruction of neurons. 8 • CD8 ‘killer’ T cells destroy axons; membrane damage in major histocompatibility complex class I restricted neurons by CD8+ T cells suggest granule-mediated death. 9–11 • Interleukin (IL)-10 producers including CD4+, CD25+ and regulatory T cells (Tregs) are able to suppress inflammation. Tregs normally act to inhibit autoreactive cells. Numbers and functional capacity of Treg cells is impaired in patients with relapsing-remitting MS (RRMS), 8,12 which allows autoreactive T cells to induce CNS damage. B cells are potent antigen-presenting cells that can contribute to the pathogenesis of MS via cytokine production, antigen presentation and formation of autoantibodies. 1,13 High levels of CD80 (B7-1) antigens on the surface of B cells permit them to activate antigen-specific cells. 14 T and B cells form clusters which lead to immune activation and the formation of adaptive memory. B cells can activate autoreactive T cells. Large B cell aggregates comprising T cells and plasma cells can form in the inflamed cerebral meninges of secondary progressive MS (SPMS) patients. 15 It is difficult to eliminate cell clusters behind the blood–brain barrier, which may explain disease progression in patients with SPMS. In MS there are complex cellular networks that drive and dampen disease pathophysiology (see Figure 1). The interactions between T and B cells provide multiple targets for MS treatments. A preferred approach in MS therapy, therefore, is to target more than one component. 1,12,16–22 TOU C H ME D ICA L ME D IA