scholarly journals Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Simone Wüst ◽  
Jens van den Brandt ◽  
Holger M. Reichardt ◽  
Fred Lühder
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Preventive Treatment ◽  
Pulse Therapy ◽  
Careful Consideration ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Peripheral T Cells ◽  
Dose Dependent ◽  
Experimental Autoimmune

Glucocorticoids (GCs) represent the standard treatment for acute disease bouts in multiple sclerosis (MS) patients, for which methylprednisolone (MP) pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application inMOG35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner. Surprisingly, MP administration around the time of immunization was contraindicated as it even increased leukocyte infiltration into the CNS and worsened the disease symptoms. Our analyses suggest that in the latter case an incomplete depletion of peripheral T cells by MP triggers homeostatic proliferation, which presumably results in an enhanced priming of autoreactive T cells and causes an aggravated disease course. Thus, the timing and selection of a particular GC derivative require careful consideration in MS therapy.

scholarly journals Peripheral T Cells Are the Therapeutic Targets of Glucocorticoids in Experimental Autoimmune Encephalomyelitis

2008 ◽  
Vol 180 (12) ◽  
pp. 8434-8443 ◽  
Author(s):  
Simone Wüst ◽  
Jens van den Brandt ◽  
Denise Tischner ◽  
Anna Kleiman ◽  
Jan P. Tuckermann ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Therapeutic Targets ◽  
Autoimmune Encephalomyelitis ◽  
Peripheral T Cells ◽  
Experimental Autoimmune

scholarly journals CXCL12 (SDF-1α) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells

2008 ◽  
Vol 205 (11) ◽  
pp. 2643-2655 ◽  
Author(s):  
Moran Meiron ◽  
Yaniv Zohar ◽  
Rachel Anunu ◽  
Gizi Wildbaum ◽  
Nathan Karin
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Neutralizing Antibodies ◽  
Regulatory Function ◽  
Th1 Cells ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell–derived factor 1α), redirects the polarization of effector Th1 cells into CD4+CD25−Foxp3−interleukin (IL) 10high antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10–deficient mice. Anti–IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4+CD25−Foxp3−IL-10high, which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig–induced tolerance is IL-10 dependent, IL-10–independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

scholarly journals Infection with Mycobacterium bovis BCG Diverts Traffic of Myelin Oligodendroglial Glycoprotein Autoantigen-Specific T Cells Away from the Central Nervous System and Ameliorates Experimental Autoimmune Encephalomyelitis

2003 ◽  
Vol 10 (4) ◽  
pp. 564-572 ◽  
Author(s):  
Diane L. Sewell ◽  
Emily K. Reinke ◽  
Dominic O. Co ◽  
Laura H. Hogan ◽  
Robert B. Fritz ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Autoimmune Disease ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Mycobacterium Bovis ◽  
Clinical Severity ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

ABSTRACT Infectious agents have been proposed to influence susceptibility to autoimmune diseases such as multiple sclerosis. We induced a Th1-mediated central nervous system (CNS) autoimmune disease, experimental autoimmune encephalomyelitis (EAE) in mice with an ongoing infection with Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) to study this possibility. C57BL/6 mice infected with live BCG for 6 weeks were immunized with myelin oligodendroglial glycoprotein peptide (MOG35-55) to induce EAE. The clinical severity of EAE was reduced in BCG-infected mice in a BCG dose-dependent manner. Inflammatory-cell infiltration and demyelination of the spinal cord were significantly lessened in BCG-infected animals compared with uninfected EAE controls. ELISPOT and gamma interferon intracellular cytokine analysis of the frequency of antigen-specific CD4+ T cells in the CNS and in BCG-induced granulomas and adoptive transfer of MOG35-55-specific green fluorescent protein-expressing cells into BCG-infected animals indicated that nervous tissue-specific (MOG35-55) CD4+ T cells accumulate in the BCG-induced granuloma sites. These data suggest a novel mechanism for infection-mediated modulation of autoimmunity. We demonstrate that redirected trafficking of activated CNS antigen-specific CD4+ T cells to local inflammatory sites induced by BCG infection modulates the initiation and progression of a Th1-mediated CNS autoimmune disease.

scholarly journals Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yan Zhou ◽  
Xiao Leng ◽  
Shasha Luo ◽  
Zhiwei Su ◽  
Xingyan Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Kinase Inhibitor ◽  
Adoptive Cell Therapy ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Concentration Dependent Manner ◽  
Experimental Autoimmune

It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.

scholarly journals A Commercial Probiotic Induces Tolerogenic and Reduces Pathogenic Responses in Experimental Autoimmune Encephalomyelitis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 906 ◽  
Author(s):  
Laura Calvo-Barreiro ◽  
Herena Eixarch ◽  
Manuel Ponce-Alonso ◽  
Mireia Castillo ◽  
Rafael Lebrón-Galán ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Therapeutic Effect ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Multiple Sclerosis Patients ◽  
Dose Dependent ◽  
Experimental Autoimmune ◽  
Experimental Disease

Previous studies in experimental autoimmune encephalomyelitis (EAE) models have shown that some probiotic bacteria beneficially impact the development of this experimental disease. Here, we tested the therapeutic effect of two commercial multispecies probiotics—Lactibiane iki and Vivomixx—on the clinical outcome of established EAE. Lactibiane iki improves EAE clinical outcome in a dose-dependent manner and decreases central nervous system (CNS) demyelination and inflammation. This clinical improvement is related to the inhibition of pro-inflammatory and the stimulation of immunoregulatory mechanisms in the periphery. Moreover, both probiotics modulate the number and phenotype of dendritic cells (DCs). Specifically, Lactibiane iki promotes an immature, tolerogenic phenotype of DCs that can directly induce immune tolerance in the periphery, while Vivomixx decreases the percentage of DCs expressing co-stimulatory molecules. Finally, gut microbiome analysis reveals an altered microbiome composition related to clinical condition and disease progression. This is the first preclinical assay that demonstrates that a commercial probiotic performs a beneficial and dose-dependent effect in EAE mice and one of the few that demonstrates a therapeutic effect once the experimental disease is established. Because this probiotic is already available for clinical trials, further studies are being planned to explore its therapeutic potential in multiple sclerosis patients.

scholarly journals Chloroquine Treatment Enhances Regulatory T Cells and Reduces the Severity of Experimental Autoimmune Encephalomyelitis

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65913 ◽  
Author(s):  
Rodolfo Thomé ◽  
Adriel S. Moraes ◽  
André Luis Bombeiro ◽  
Alessandro dos Santos Farias ◽  
Carolina Francelin ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Chloroquine Treatment ◽  
Experimental Autoimmune

scholarly journals Mgat5 Deficiency in T Cells and Experimental Autoimmune Encephalomyelitis

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Ani Grigorian ◽  
Michael Demetriou
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Demyelinating Disease ◽  
Cell Receptor ◽  
Protein Glycosylation ◽  
Autoimmune Encephalomyelitis ◽  
Glycosylation Pathway ◽  
Experimental Autoimmune ◽  
Surface Glycoproteins

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease initiated by autoreactive T cells. Mgat5, a gene in the Asn (N-) linked protein glycosylation pathway, associates with MS severity and negatively regulates experimental autoimmune encephalomyelitis (EAE) and spontaneous inflammatory demyelination in mice. N-glycan branching by Mgat5 regulates interaction of surface glycoproteins with galectins, forming a molecular lattice that differentially controls the concentration of surface glycoproteins. T-cell receptor signaling, T-cell proliferation, TH1 differentiation, and CTLA-4 endocytosis are inhibited by Mgat5 branching. Non-T cells also contribute to MS pathogenesis and express abundant Mgat5 branched N-glycans. Here we explore whether Mgat5 deficiency in myelin-reactive T cells is sufficient to promote demyelinating disease. Adoptive transfer of myelin-reactive Mgat5−/− T cells into Mgat5+/+ versus Mgat5−/− recipients revealed more severe EAE in the latter, suggesting that Mgat5 branching deficiency in recipient naive T cells and/or non-T cells contribute to disease pathogenesis.

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