Statistical analysis of data from studies on experimental autoimmune encephalomyelitis

Fleming, Kandace; Bovaird, James A.; Mosier, Michael; Emerson, Mitchell R.; Levine, Steven M.; Marquis, Janet

doi:10.1016/j.jneuroim.2005.08.020

Cited by 82 publications

(80 citation statements)

References 26 publications

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“…Additionally, animals receiving the combination therapy had a significantly lower area under the curve measure (AUC) for clinical scores, an indicator of less severe disease overall (Fig. 5B) (63). Together with our studies in vitro, these in vivo data suggest that T-614 may have promise as a steroid-sparing therapy.…”

Section: Cytokine Release By Monocytes Different Profiles Of Mifsupporting

confidence: 52%

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Bloom

Metz

Nalawade

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerMacrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in a broad range of inflammatory and oncologic diseases. MIF is unique among cytokines in terms of its release profile and inflammatory role, notably as an endogenous counter-regulator of the anti-inflammatory effects of glucocorticoids. In addition, it exhibits a catalytic tautomerase activity amenable to the design of high affinity small molecule inhibitors. Although several classes of these compounds have been identified, biologic characterization of these molecules remains a topic of active investigation. In this study, we used in vitro LPS-driven assays to characterize representative molecules from several classes of MIF inhibitors. We determined that MIF inhibitors exhibit distinct profiles of anti-inflammatory activity, especially with regard to TNF␣. We further investigated a molecule with relatively low anti-inflammatory activity, compound T-614 (also known as the anti-rheumatic drug iguratimod), and found that, in addition to exhibiting selective MIF inhibition in vitro and in vivo, iguratimod also has additive effects with glucocorticoids. Furthermore, we found that iguratimod synergizes with glucocorticoids in attenuating experimental autoimmune encephalitis, a model of multiple sclerosis. Our work identifies iguratimod as a valuable new candidate for drug repurposing to MIF-relevant diseases, including multiple sclerosis.

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Section: Cytokine Release By Monocytes Different Profiles Of Mifsupporting

confidence: 52%

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Bloom

Metz

Nalawade

et al. 2016

Journal of Biological Chemistry

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“…Hence, the surgical protocol and imaging session do not influence the day when animals first display symptoms or reach their highest clinical score. To evaluate the total severity of EAE, the area under the curve and maximal clinical score attained were used as summary statistics to compare individual animals (54). Both parameters were identical between the two groups (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

182

159

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Disruption of the blood–brain and blood–spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP+ myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP+ cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

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“…Outcome measures and alphawise error-Typically, EAE studies assess some or all of the following four disease severity measures (Fleming et al, 2005): 1) day of onset, calculated by counting the number of days from immunization to the day that the first sign of disease is displayed by an animal; 2) day of maximum (peak) disease severity, calculated by counting the number of days from immunization to the day that an animal is rated at its maximum disease severity; 3) maximum disease severity, calculated by determining the maximum disease severity score for a given animal; and 4) cumulative disease index (CDI), calculated by summing the disease severity score for each day for an animal.…”

Section: Methodsmentioning

confidence: 99%

Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning

Jones

Moes

Zwickey

et al. 2008

Brain, Behavior, and Immunity

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We have initiated studies to evaluate the suitability of performing therapeutic conditioning trials in experimental autoimmune encephalomyelitis (EAE) mice treated with alpha lipoic acid (ALA). EAE was induced in SJL mice by active immunization with myelin antigen. Once daily subcutaneous injection of ALA served as the unconditional stimulus (US) administered with the conditional stimulus (CS) saccharin-flavored drinking water under a regimen of restricted water access. In the first study, we found that water restriction and saccharin administration were compatible with disease development and effective ALA treatment of EAE mice. In the second study, mice were conditioned to once daily administration of ALA paired with administration of saccharin flavored water (US + CS) on days 7 -16. Test trials spanned experimental days 17 -32 in groups receiving either saccharinflavored water (CS, in the experimental group) versus unflavored water (CSo, in the control group) and compared several measures of EAE severity using multivariate ANOVA (MANOVA). Reduced disease severity in the experimental group (US+CS:CS) compared to the control group (US+CS:CSo) suggested that conditioning had occurred. These results demonstrate an approach for conducting therapeutic conditioning trials in EAE mice and suggest considerations for future investigations.

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Statistical analysis of data from studies on experimental autoimmune encephalomyelitis

Cited by 82 publications

References 26 publications

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning

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