Clinical, electrophysiological and pathologic correlations in a severe murine experimental autoimmune neuritis model of Guillain–Barré syndrome☆

Xia, Robin H.; Yosef, Nejla; Ubogu, Eroboghene E.

doi:10.1016/j.jneuroim.2009.11.019

Cited by 36 publications

(85 citation statements)

References 29 publications

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“…Another Lewis rat EAN study demonstrated that the highest number of CCR2+ mononuclear cells infiltrating into the sciatic nerve endoneurium was associated with peak clinical paralysis [30], further implying a role for CCL2/CCR2 interactions in the pathogenesis of EAN. We recently characterized a severe murine EAN that recapitulates the clinical, electrophysiological and pathologic features of severe demyelinating forms of GBS [31]. We have demonstrated increased expression of chemokines CCL2, CCL5 and CXCL10 and receptors CCR1, CCR2, CCR5 and CXCR3 in the sciatic nerves of affected mice relative to controls [32].…”

Section: Autoimmune Neuropathiesmentioning

confidence: 93%

“…Our recent development of an in vitro model of the human blood-nerve barrier [60] and advancements in murine AIN models (e.g. severe murine-EAN in Swiss Jim Lambert mice and spontaneous autoimmune peripheral polyneuropathy in CD86 deficient non-obese diabetic mice, a model of CIDP) [31,32,61], as well as advancements by others using rodent models of neuropathic pain should aid in deducing the roles of specific chemokine ligand-receptors pairs in these disorders. Such work will provide the necessary proof-of principle pre-requisite needed to initiate early phase clinical trials of chemokine receptor antagonists in GBS/CIDP and neuropathic pain.…”

Section: Chemokine Receptor Antagonists In Human Disordersmentioning

confidence: 99%

“…Macrophages are the most prevalent leukocyte subpopulation observed in affected peripheral nerves in GBS and CIDP, and their animal models [9,10,16,31]. CCR2 inhibition could restrict macrophage infiltration to damaged axons as well as migration to dorsal root ganglion neurons following peripheral nerve injury; processes implicated in peripheral nerve sensitization and neuropathic pain.…”

Section: Where Do We Start In Peripheral Nerve Inflammation and Neuromentioning

confidence: 99%

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Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Ubogu

2011

EMIDDT

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Chemokines are the initial mediators of leukocyte migration across concentration gradients in vitro and to sites of inflammation in vivo. Chemokines signal via specific seven-transmembrane spanning G-protein coupled receptors (GPCRs). About 50 chemokine ligands and 18 receptors have been identified to date, and several are involved in leukocyte trafficking in human inflammation. Several chemokines signal via a single receptor, while others signal via multiple receptors. This redundancy may be necessary to mediate essential biological processes in vivo. There is evidence that specific chemokines and their receptors are expressed in the peripheral nerves or cerebrospinal fluid of patients with autoimmune neuropathies such as Guillain-Barré syndrome and Chronic Inflammatory Demyelinating Polyradiculoneuropathy and their animal models. Hematogenous leukocyte trafficking and chemokine-mediated signaling has also been implicated in the generation of neuropathic pain following peripheral nerve injury. Chemokine receptors, being GPCRs, provide an attractive drug target for modulating the harmful effects of peripheral nerve inflammation. The efficacy of anti-inflammatory therapies, including treatments that restrict leukocyte migration, has been established in several inflammatory disorders such as multiple sclerosis. There are several ongoing clinical trials testing chemokine receptor antagonists as specific anti-inflammatory drugs. This review evaluates the current status of the chemokine biology of peripheral neuropathies, highlighting areas where further studies are needed and discusses potentially selective drug targets for peripheral nerve inflammation and neuropathic pain.

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Section: Autoimmune Neuropathiesmentioning

confidence: 93%

Section: Chemokine Receptor Antagonists In Human Disordersmentioning

confidence: 99%

Section: Where Do We Start In Peripheral Nerve Inflammation and Neuromentioning

confidence: 99%

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Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Ubogu

2011

EMIDDT

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“…Sm-EAN was induced in 8–12 week old, non-pregnant female mice using purified bovine peripheral nerve myelin emulsified in complete Freund adjuvant, with pertussis toxin and recombinant mouse interleukin-12 serving as co-adjuvants, as previously described [34,39]. Four independent experiments using a total of 83 age-matched mice were conducted to determine the effect of CD11b antibody blockade on sm-EAN and establish a dose-response relationship, followed by comparative studies using vehicle (phosphate buffered saline [PBS])- and isotype antibody-treated mice as negative controls, and human IVIg (gold standard GBS treatment) as a positive control.…”

Section: Methodsmentioning

confidence: 99%

The pathogenic relevance of αM-integrin in Guillain–Barré syndrome

et al. 2016

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The molecular determinants and mechanisms involved in leukocyte trafficking across the blood-nerve barrier (BNB) in the Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) variant of Guillain-Barré syndrome are incompletely understood. Prior work using a flow-dependent in vitro human BNB model demonstrated a crucial role for αM-integrin (CD11b)-intercellular adhesion molecule-1 interactions in AIDP patient leukocyte trafficking. The aim of this study is to directly investigate the biological relevance of CD11b in AIDP pathogenesis. Immunohistochemistry was performed on three AIDP patient sural nerve biopsies to evaluate endoneurial leukocyte CD11b expression. A severe murine experimental autoimmune neuritis (sm-EAN) model was utilized to determine the functional role of CD11b in leukocyte trafficking in vivo and determine its effect on neurobehavioral measures of disease severity, electrophysiological assessments of axonal integrity and myelination and histopathological measures of peripheral nerve inflammatory demyelination. Time-lapse video microscopy and electron microscopy were employed to observe structural alterations at the BNB during AIDP patient leukocyte trafficking in vitro and in situ respectively. Large clusters of endoneurial CD11b+ leukocytes associated with demyelinating axons were observed in AIDP patient sural nerves. Leukocyte CD11b expression was upregulated during sm-EAN. 5mg/kg of a function-neutralizing monoclonal rat-anti mouse CD11b antibody administered after sm-EAN disease onset significantly ameliorated disease severity, as well as electrophysiological and histopathological parameters of inflammatory demyelination compared to vehicle- and isotype antibody-treated mice. Consistent with in vitro observations of leukocyte trafficking at the BNB, electron micrographs of AIDP patient sural nerves demonstrated intact electron-dense endoneurial microvascular intercellular junctions during paracellular mononuclear leukocyte transmigration. Our data supports a crucial pathogenic role of CD11b in AIDP leukocyte trafficking, providing a potential therapeutic target for demyelinating variants of Guillain-Barré syndrome.

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“…Experimental autoimmune neuritis (EAN) is a CD4+ T helper 1 (Th1) cell-mediated inflammatory demyelinating disease of the peripheral nervous system (PNS) that mirrors many clinical and immunological features of human acute inflammatory demyelinating polyradiculoneuropathies. EAN serves as the canonical animal model to study GBS [6].…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone, PPARγ Agonist, Attenuates Experimental Autoimmune Neuritis

et al. 2012

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Recent advances demonstrate peroxisome proliferator-activated receptors gamma (PPARγ) agonist, pioglitazone, as an anti-inflammatory drug. We investigated the effect of pioglitazone on experimental autoimmune neuritis (EAN) rats. Pioglitazone was given once daily (10 mg/kg) by oral gavage feeding from day 1-24 (suppressive group) and day 11-24 (therapeutic group). Pioglitazone ameliorated the clinical score of EAN, decreased expression of TNF-α, IFN-γ, and the activation of NF-κB, while increasing the expression of PPARγ and IL-4. Furthermore, we observed higher expression of PPARγ and IL-4 and lower expression of TNF-α, IFN-γ and reduced activation of NF-κB in suppressive group than those in the therapeutic group, which corresponds to lower clinical score and earlier disease recovery. Our data effectively demonstrate the anti-inflammatory properties of pioglitazone in EAN by inhibition of NF-κB signaling pathway.

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Clinical, electrophysiological and pathologic correlations in a severe murine experimental autoimmune neuritis model of Guillain–Barré syndrome☆

Cited by 36 publications

References 29 publications

Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

The pathogenic relevance of αM-integrin in Guillain–Barré syndrome

Pioglitazone, PPARγ Agonist, Attenuates Experimental Autoimmune Neuritis

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