Regulation of human glia by multiple sclerosis disease modifying therapies

Abstract

This review focuses on the effects of the agents currently approved (or in late clinical trials) as therapies for multiple sclerosis (MS) on the glial cell populations of the central nervous system (CNS). These are comprised of astrocytes, microglia, and oligodendrocytes (OLs), and their progenitors (OPCs). Although the efficacy of these agents is to date established only for the relapsing component of the disease and linked to effects on the systemic immune system, each has been examined with regard to effects on the CNS compartment. The impact of therapies on glia would include modulating these cells immune reactivity, which is considered to underlie the tissue injury process in MS and to any subsequent repair process. As reviewed, these agents can exert their effects either indirectly by modulating the constituents of the systemic immune system or directly depending on their capacity to traverse the blood brain barrier (BBB). Most available data has been derived from administration of these agents in animal models or application to glial cells in vitro. The challenge remains of translating these observations into effective means to impact on the progressive course of disease and reverse existent disabilities.

Microglia in Multiple Sclerosis: Friend or Foe?

“…Current disease modifying therapies (DMT) have been shown to have a modest effect on microglia and are divided into indirect and direct effects (73,74). Interferon beta and glatiramer acetate exert an indirect effect by inducing a Th2 shift in lymphocyte profile thereby reducing the pro-inflammatory phenotype of microglia (73,74).…”

“…Current disease modifying therapies (DMT) have been shown to have a modest effect on microglia and are divided into indirect and direct effects (73,74). Interferon beta and glatiramer acetate exert an indirect effect by inducing a Th2 shift in lymphocyte profile thereby reducing the pro-inflammatory phenotype of microglia (73,74). Interferon beta suppresses interferon gamma induced MHC class II expression on microglia but paradoxically increases the production of inflammatory mediators such as TNF-α, IL-1β, IL-6, and NO (75,76).…”

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

“…According to the orthodox narrative, FTY720 exerts anti-inflammatory effects by blocking lymphocyte egress from lymph nodes, causing peripheral lymphopenia and interrupting traffic to the CNS of auto-reactive T cells (Brunkhorst, Vutukuri, & Pfeilschifter, 2014; Chun & Hartung, 2010; Cohen & Chun, 2011; Mehling et al, 2011). However, in MS, other neuroinflammatory pathologies and their experimental models, there is often a poor correlation between lymphopenia and the beneficial effects of FTY720 and related compounds, suggesting that additional mechanism of action are likely to be important (Choi et al, 2011; Foster et al, 2007; Healy, Michell-Robinson, & Antel, 2015; La Mantia et al, 2016; Rothhammer et al, 2017; Serdar et al, 2016). In fact, beneficial effect of FTY720 have been demonstrated in a variety of CNS resident cells, including astrocytes, microglia, oligodendrocytes and vascular endothelial cells (Groves, Kihara, & Chun, 2013; Miron, Schubart, & Antel, 2008).…”

Identification of the Lipid Antigens Recognized by rHIgM22, a Remyelination-Promoting Antibody

“…As of now there is no actual cure for MS, and the current FDA approved therapies mainly target the in ammatory component, in order to contain myelin damage. Some of these strategies however, for example the use of Fingolimod, are also able to increase the e ciency of the remyelination process [52][53][54][55]. In most mouse models, remyelination is a spontaneous process, occurring in response to demyelination, and leads to functional recovery.…”