Current Treatment Strategies for Multiple Sclerosis - Efficacy Versus Neurological Adverse Effects
Department of Neurology, Technische Universität München, Munich, Germany. Current pharmaceutical design
(Impact Factor: 3.45).
02/2012; 18(2):209-19. DOI: 10.2174/138161212799040501
Recent years have broadened the spectrum of therapeutic strategies and specific agents for treatment of multiple sclerosis (MS). While immune-modulating drugs remain the first-line agents for MS predominantly due to their benign safety profile, our growing understanding of key processes in initiation and progression of MS has pioneered development of new agents with specific targets. One concept of these novel drugs is to hamper migration of immune cells towards the affected central nervous system (CNS). The first oral drug approved for MS therapy, fingolimod inhibits egress of lymphocytes from lymph nodes; the monoclonal antibody natalizumab prevents inflammatory CNS infiltration by blocking required adhesion molecules. The second concept is to deplete T cells and/or B cells from the peripheral circulation using highly specific monoclonal antibodies such as alemtuzumab (anti-CD52) or rituximab/ocrelizumab (anti-CD20). All of these novel, highly effective agents are a substantial improvement in our therapeutic armamentarium; however, they have in common to potentially lower the abundance of immune cells within the CNS, thereby collaterally affecting immune surveillance within this well-controlled compartment. In this review, we aim to critically evaluate the risk/benefit ratio of therapeutic strategies in treatment of MS with a specific focus on infectious neurological side effects.
Available from: Shlomo Rotshenker
- "Anti-inflammatory agents primarily suppress synchronized CNS infiltration causing relapses, while smoldering inflammation within the CNS causing progressive MS is still in need of good therapy. Some of the existing agents cause serious side effects, running a risk of opportunistic infections or secondary autoimmunity (Br€ uck et al., 2013; Coles et al., 1999; Cossburn et al., 2011; Langer-Gould et al., 2005; Weber et al., 2012). A search for alternative anti-inflammatory compounds should thus also consider novel targets. "
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ABSTRACT: The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll-like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR-induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti-inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN-sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions.GLIA 2015.
© 2015 Wiley Periodicals, Inc.
Glia 03/2015; 63(6). DOI:10.1002/glia.22803 · 6.03 Impact Factor
Available from: Damir Janigro
- "The unique feature of anti-SEMA4D therapy is that it combines independent mechanisms of action that overlap with the anti-inflammatory effects of several of these clinical agents and further extends activity to restoring and protecting the integrity of both BBB and myelinated axons. While approved immunosuppressive and anti-inflammatory drugs have been shown to be effective in transiently suppressing MS-related symptoms and relapse frequency, many have significant side-effects with varying degrees of severity (Weber et al., 2012). In animal studies and ongoing phase 1 clinical trials to date, anti-SEMA4D antibody administration has not been associated with significant overt toxicity. "
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ABSTRACT: Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood–brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit.
Neurobiology of Disease 10/2014; 73. DOI:10.1016/j.nbd.2014.10.008 · 5.08 Impact Factor
Available from: Debayon Paul
- "Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by infiltration of peripheral immune cells into the CNS through an impaired blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB), and loss of myelin with accompanying scarring of axons (McFarland and Martin, 2007). However, most current treatments for MS only offer palliative relief without providing a cure, and many are also associated with adverse effects that limit their long-term utility (Weber et al., 2012). "
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ABSTRACT: Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.
Stem Cell Reports 07/2014; 3(1):1-16. DOI:10.1016/j.stemcr.2014.04.020 · 5.37 Impact Factor
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