Critical appraisal of animal models of multiple sclerosis

Baker, David; Gerritsen, Wouter; Rundle, Jon; Amor, Sandra

doi:10.1177/1352458511398885

Cited by 90 publications

(92 citation statements)

References 68 publications

(157 reference statements)

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“…This observation correlates with a clinical study which found that MS patients with Frontiers in Microbiology | Microbial Immunology positive H. pylori serology tests had lower disability scores than seronegative patients (Mohebi et al, 2013). Infiltration of leukocytes into the CNS has been shown to correlate with lesion load within the spinal cord of EAE mice (Baker et al, 2011). Those infected with H. pylori had markedly reduced numbers of Th1 and Th17 cells in both the CNS and spleen.…”

Section: Discussionsupporting

confidence: 74%

“…MS is an inflammatory demyelinating immune-mediated disorder which affects the central nervous system (CNS). Development of autoreactive T cell responses against CNS-derived antigens leads to infiltration of Th1 and Th17 cells into the CNS (Goverman, 2009;Baker et al, 2011), resulting in damage to the myelin sheath of neural axons, inflammation, and neurodegeneration (Frohman et al, 2006). Studies have shown that the balance between pro-inflammatory Th1 and Th17 responses and anti-inflammatory Treg responses, either in terms of numbers or functional activity, are important in MS development and progression (Edstrom et al, 2011;Sellebjerg et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

Gran

Crooks

Cook³

et al. 2015

Journal of the Neurological Sciences

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Recent research has demonstrated that infection with the bacterial pathogen Helicobacter pylori is less common amongst patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). We aimed to compare the prevalence of H. pylori amongst MS patients and healthy controls, and also investigated the impact of this infection on an animal model for MS, experimental autoimmune encephalomyelitis (EAE). The H. pylori status of 71 MS patients and 42 healthy controls was determined by serology. Groups of C57BL/6 mice were infected with H. pylori, or given diluent alone as a placebo, prior to inducing EAE. Clinical scores were assessed for all mice, and spleens and spinal cord tissue were harvested. CD4 + T cell subsets were quantified by flow cytometry, and T cell proliferation assays were performed. In MS patients the seroprevalence of H. pylori was half that of healthy controls (p = 0.018). Over three independent experiments, prior H. pylori infection had a moderate effect in reducing the severity of EAE (p = 0.012). In line with this, the antigen-specific T cell proliferative responses of infected animals were significantly reduced (p = 0.001), and there was a fourfold reduction in the number of CD4 + cells in the CNS. CD4 + populations in both the CNS and the spleens of infected mice also contained greatly reduced proportions of IFNγ + , IL-17 + ,T-bet + , and RORγt + cells, but the proportions of Foxp3 + cells were equivalent.There were no differences in the frequency of splenic CD4 + cells expressing markers of apoptosis between infected and uninfected animals. H. pylori was less prevalent amongst MS patients. In mice, the infection exerted some protection against EAE, inhibiting both Th1 and Th17 responses. This could not be explained by the presence of increased numbers of Foxp3 + regulatory T cells, or T cell apoptosis. This is the first direct experimental evidence showing that H. pylori may provide protection against inflammatory demyelination in the CNS.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis

Gran

Crooks

Cook³

et al. 2015

Journal of the Neurological Sciences

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“…Although numerous T cell directed therapies significantly reduce disease severity in this model [8,9], T cell depletion with anti-CD3 and anti-CD4 monoclonal antibodies failed in clinical trials for MS [10,11]. Depletion of peripheral B cells with anti-CD20 monoclonal antibodies in EAE enhances or inhibits disease severity dependent upon the time of dosing and the specific EAE model used.…”

Section: Introductionmentioning

confidence: 99%

B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

Jackson

Selva²,

Niedzielko³

et al. 2014

J Clin Cell Immunol

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Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) leading to neuronal demyelination, lack of remyelination, and axonal loss. If left untreated, patients inevitably suffer from severe cognitive, psychological and physical disabilities.Although not yet approved, B cell depletion achieved with anti-CD20 monoclonal antibodies is the most effective therapy to-date in MS patients. As this therapeutic depletes immune cells potentially important in pathogen immunity, an immense need remains for highly efficacious therapeutics maintaining a favorable safety profile. Even amongst the emergence of new therapeutic options for patients with MS, the myelin basic protein mimetic, Copaxone (glatiramer acetate, GA), remains the most commonly prescribed drug in the United States. As specific B cell depletion appears to be the most effective therapy for MS patients, the goal of this study was to further elucidate the mechanism of action of GA on B lymphocytes. Our studies show that GA directly interacts with human and murine B cell receptors (BCR) inducing the activation of B lymphocytes and BCR recognition of GA is required for efficacy in an animal model of MS. GA loaded B lymphocytes resulted in IL-2 production from CD4 + T cells suggesting B lymphocytes serve as an antigen presentation source for GA. In fifty-percent of the MS patients tested, GA stimulation reduced baseline levels of the pro-inflammatory cytokines IL-6 and TNFα in purified B lymphocytes, while other cytokines were not consistently altered. Taken together, this data suggests that the mechanism of action of GA on B lymphocytes includes the presentation of GA to T lymphocytes in the context of an anti-inflammatory cytokine milieu. The results from this study provide a strong foundation for future exploration of optimal Copaxone responders or synergistic combination therapies with an improved risk: benefit ratio compared to currently approved therapeutics for MS.

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“…One recent example that is highly relevant to neurology is the development of contemporary immunomodulatory treatments for multiple sclerosis based on preliminary studies in a CNS autoimmune disorder induced experimentally in animals. 4 Continuing identification of innovative therapies using animal models is anticipated in the future as a result of increasingly sophisticated molecular genetic, stem cell, and epigenetic research programs. 5 Animal research continues to be critical for protecting patients from premature approval of potentially deleterious drugs.…”

mentioning

confidence: 99%

“…8,10 Telephone and e-mail harassment, vandalism (broken windows, flooding), home invasion, and firebombing have all been documented as methods of intimidating scientists engaged in animal research. 4 In January 1990, the University of Tennessee received a letter from anti-animal research extremists threatening to assassinate a veterinary dean within 12 months. One month later, the dean of the veterinary school at the University of Tennessee died as a result of a gunshot wound received while on his private farm.…”

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confidence: 99%