Glatiramer acetate for treatment of MS: Regulatory B cells join the cast of players

Kaer, Luc Van

doi:10.1016/j.expneurol.2010.10.009

Cited by 16 publications

(8 citation statements)

References 55 publications

(90 reference statements)

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“…In light of depletion therapy success, more focus is now being given to B-cells and their role in MS. The literature supports both a pathogenic (72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82) and regulatory (76,(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94) role for B-cells in MS/EAE, and it is intriguing to speculate about the potential immune cell interplay between CD4 + T-cells, B-cells, and CD8 + T-cells therein. There is evidence in the literature to support a B-cell effect on CD8 + T-cells (54,55,82,(95)(96)(97)(98)(99)(100).…”

Section: Potential Cd8 + T-cell: B-cell Interactions In Ms/eae?mentioning

confidence: 94%

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

et al. 2015

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The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4+ T-cells as mediators and regulators of disease. Interestingly, CD8+ T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial. Several animal models and MS patient studies support a pathogenic role for CNS-specific CD8+ T-cells, whereas we and others have demonstrated a regulatory role for these cells in disease. In this review, we describe studies that have investigated the role of CD8+ T-cells in MS and EAE, presenting evidence for both pathogenic and regulatory functions. In our studies, we have shown that cytotoxic/suppressor CD8+ T-cells are CNS antigen-specific, MHC class I-restricted, IFNγ- and perforin-dependent, and are able to inhibit disease. The clinical relevance for CD8+ T-cell suppressive function is best described by a lack of their function during MS relapse, and importantly, restoration of their suppressive function during quiescence. Furthermore, CD8+ T-cells with immunosuppressive functions can be therapeutically induced in MS patients by glatiramer acetate (GA) treatment. Unlike CNS-specific CD8+ T-cells, these immunosuppressive GA-induced CD8+ T-cells appear to be HLA-E restricted. These studies have provided greater fundamental insight into the role of autoreactive as well as therapeutically induced CD8+ T-cells in disease amelioration. The clinical implications for these findings are immense and we propose that this natural process can be harnessed toward the development of an effective immunotherapeutic strategy.

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Section: Potential Cd8 + T-cell: B-cell Interactions In Ms/eae?mentioning

confidence: 94%

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

et al. 2015

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“…Independent of the idea that Bregs constitute a true cell lineage or merely a state of activation by B cells, the production of IL-10 by a subset of B cells has proven critical for the resolution of EAE and other autoimmune disorders both in mice and humans (6, 10, 11, 21, 69). Bregs also have a role in the mechanism of action by Copaxone ® , a glatiramer acetate copolymer, approved for the treatment of relapsing-remitting MS (5, 12, 25, 52, 56). In a recent clinical trial, Ireland et al showed that treatment of relapsing-remitting MS patients with glatiramer acetate restored IL-10 production while reducing lymphotoxin-α production by peripheral B cells, thus contributing to the therapeutic effects of glatiramer acetate (53).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis

Huarte

Jun

Rynda‐Apple

et al. 2016

The Journal of Immunology

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Regulatory T cells (Tregs) induced during autoimmunity often become quiescent and unable to resolve disease, suggesting inadequate activation. Resolution of established experimental autoimmune encephalomyelitis (EAE) can be achieved with myelin oligodendrocyte glycoprotein (MOG) fused to reovirus protein σ1 (MOG-pσ1) which activates Tregs, restoring protection, but requiring other regulatory cells to revitalize them. B cells have a dichotomous role in both the pathogenesis and recovery from EAE. While inflammatory B cells contribute to EAE’s pathogenesis, treatment of EAE mice with MOG-pσ1, but not OVA-pσ1, resulted in an influx of IL-10-producing B220+CD5+ B regulatory cells (Bregs) enabling Tregs to recover their inhibitory activity, and in turn, leading to the rapid amelioration of EAE. These findings implicate direct interactions between Bregs and Tregs to facilitate this recovery. Adoptive transfer of B220+CD5− B cells from MOG-pσ1-treated EAE or Bregs from PBS-treated EAE mice did not resolve disease while the adoptive transfer of MOG-pσ1-induced B220+CD5+ Bregs greatly ameliorated EAE. MOG-pσ1-, but not OVA-pσ1-induced IL-10-producing Bregs, expressed elevated levels of BTLA relative to CD5− B cells, as opposed to Tregs or effector T (Teff) cells, whose BTLA expression was not affected. These induced Bregs restored EAE Treg function in a BTLA-dependent manner. BTLA−/− mice showed more pronounced EAE with fewer Tregs but, upon adoptive transfer of MOG-pσ1-induced BTLA+ Bregs, BTLA−/− mice were protected against EAE. Hence, this evidence shows the importance of BTLA in activating Tregs to facilitate recovery from EAE.

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“…84,85 Bregs have also been implicated in the beneficial effects of glatiramer acetate against EAE. 86,87 In addition to IL-10, other mechanisms have been proposed for the suppressive functions of Bregs in EAE 88,89 and these include the induction of IL-10-producing Tregs 90 and the production of TGF-β, IL-35, programmed death 1 ligand 1 or Fas ligand. 88,89 Although most studies have implicated adaptive Bregs in these activities, they were unable to exclude a potential contribution of innate-like Bregs.…”

Section: Adaptive Lymphocytesmentioning

confidence: 99%

Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE

et al. 2019

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons. A hallmark of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), is autoimmunity against proteins of the myelin sheath. Most studies in this field have focused on the roles of CD4 + T lymphocytes, which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis. Consequently, the treatments for MS often target the inflammatory CD4 + T-cell responses. However, many other lymphocyte subsets contribute to the pathophysiology of MS and EAE, and these subsets include CD8 + T cells and B cells of the adaptive immune system, lymphocytes of the innate immune system such as natural killer cells, and subsets of innate-like T and B lymphocytes such as γδ T cells, natural killer T cells, and mucosal-associated invariant T cells. Several of these lymphocyte subsets can act as mediators of CNS inflammation, whereas others exhibit immunoregulatory functions in disease. Importantly, the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4 + T cells. Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE, with an emphasis on lymphocytes other than CD4 + T cells. A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.

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Glatiramer acetate for treatment of MS: Regulatory B cells join the cast of players

Cited by 16 publications

References 55 publications

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

CD8+ T-Cells as Immune Regulators of Multiple Sclerosis

Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis

Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE

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