Chronic experimental allergic neuritis: An electrophysiological and histological study in the rabbit

doi:10.1016/0022-510X(87)90097-9

Journal of the Neurological Sciences

Volume 81, Issues 2–3, November 1987, Pages 215-225

https://doi.org/10.1016/0022-510X(87)90097-9 Get rights and content

Abstract

Ten adult outbred New Zealand white rabbits were inoculated with a single multiportal dose of purified bovine peripheral nerve myelin and Freund's adjuvant containing 500 mg of nerve antigen. Seven animals developed chronic relapsing or progressive disease which was followed by clinical examination for 14 months. Electrophysiological studies showed marked slowing of motor conduction velocity, dispersion of the evoked muscle action potential (MAP) and reduction in amplitude of the MAP derived from distal stimulation. Histological examination of the peripheral nervous system showed at 12 months a marked hypertrophic neuropathy in the nerve roots with well developed onion bulbs, active demyelination and a moderate nerve fibre loss. It is suggested that these animals provide a reliable and predictable model for human chronic inflammatory demyelinating polyneuropathy (CIDP) which should prove valuable for therapeutic trials and studies of pathogenetic mechanisms.

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In spite of an active research performed over decades in this field, CIDP effectively remains difficult to mimic in a proven, robust experimental animals and nowadays, we must admit that no consensus has been reached in the scientific community to this regard [32,35–37]. A relevant chronic EAN model induced by immunization with purified bovine PNS myelin and closely resembling CIDP, according to electrophysiological and histological data, has been described in rabbits [38]. Experimental rabbits, however, are poorly adapted to the need of preclinical studies designed for the screening of potential pharmaceutical compounds.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nerves evolving with diffuse sensory and motor symptoms. Although it is claimed that in neurodegenerative pathologies, a common feature is the failure of proteolytic systems to adequately eliminate aggregated or misfolded proteins, it has not been addressed whether autophagy, a central “clearance” system delivering damaged intracellular components to lysosomes, is affected in CIDP. The focus of the present investigation was therefore to determine if some defects exist in autophagy processes in this setting and if they can be corrected or minimized using an appropriate treatment targeting this survival pathway. Experiments were performed using a rat model mimicking human CIDP, also known as chronic experimental autoimmune neuritis (c-EAN), the disease establishment and development of which was followed at both the clinical and biological levels (indices of disease severity, histopathological alteration, cytokines and antibodies rates). Based on immunofluorescence and western immunoblotting experiments on sciatic nerves and spleen cells from c-EAN rats, we demonstrate that both, macroautophagy and chaperone-mediated autophagy (CMA), are significantly altered in non-neuronal cells of the peripheral nervous system. We show further that a 21-mer synthetic phosphopeptide called P140, known to target CMA and successfully used in pathological settings where CMA markers are overexpressed, considerably ameliorates the clinical and biological course of the disease in c-EAN rats. P140 displayed prophylactic and therapeutic effects, both in terms of disease intensity and chronicity, and preserved sciatic nerves from disease-related damages. Our findings uncover new disrupted molecular pathways in a c-EAN model and provide a proof-of-concept that targeting CMA might represent a promising therapeutic strategy for treating inflammatory neuropathies for which no disease-specific treatment is currently available.
Characterization of a new rat model for chronic inflammatory demyelinating polyneuropathies
2015, Journal of Neuroimmunology
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CIDP is more difficult to mimic in animal models and in spite of active research in the field, no animal model for CIDP has reached common use (Salomon et al., 2001; Meyer zu Hörste et al., 2007; Soliven, 2012). A relevant chronic EAN model closely resembling CIDP (as shown by electrophysiologic and histologic data), has been described in rabbits following immunization with purified bovine PNS myelin (Harvey et al., 1987), but rabbits are less convenient to use in preclinical studies. More recently, spontaneous autoimmune polyneuropathy (SAP) in B7-2-deficient non-obese diabetic (NOD) mice, which has some similarities to the human disease and represents an alternative model of CIDP, has been characterized: in this model, the mice are protected from diabetes, and all the females exhibit limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves without spontaneous recovery (Salomon et al., 2001).
Our objective was to develop a chronic model of EAN which could be used as a tool to test treatment strategies for CIDP. Lewis rats injected with S-palmitoylated P0(180–199) peptide developed a chronic, sometimes relapsing–remitting type of disease. Our model fulfills electrophysiological criteria of demyelination with axonal degeneration, confirmed by immunohistopathology. The late phase of the chronic disease was characterized by accumulation of IL-17⁺ cells and macrophages in sciatic nerves and by high serum IL-17 levels. In conclusion, we have developed a reliable and reproducible animal model resembling CIDP that can now be used for translational drug studies.
Pathophysiology and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathies
2014, Revue Neurologique
Citation Excerpt :
The severity of EAN lesion, after P0 sensitization, can be reduced by injection of soluble tumor necrosis factor receptor (TNF-R) or interleukin 18 (IL-18) neutralizing antibodies, pointing out a key role of Th-1 cytokine responses [41,42]. Models of EAN with chronic or relapsing-remitting course have been obtained with high dose of bovine myelin injection or repeated injections [43,44]. Kremer et al., described a model of EAN with chronic evolution induced by active immunization with a thiopalmitoylated peptide S-palmP0 (180–199) [45].
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired dysimmune disorder characterized by strong heterogeneity in terms of clinical manifestations, prognostic and response to treatment. To date, its pathophysiology and potential target antigens are not totally identified despite substantial progress in the understanding of the involved molecular mechanisms. Recent researches in the field have underlined the importance of cell-mediated immunity (lymphocytes T CD4+, CD8+ and macrophages), the breakdown of blood-nerve barrier, a failure of T-cell regulation, and the disruption of nodal and paranodal organization at the node of Ranvier. This last point is possibly mediated by autoantibodies towards axoglial adhesion molecules which may disrupt sodium and potassium voltage-gated channels clustering leading to a failure of saltatory conduction and the apparition of conduction blocks. The purpose of this article is to overview the main pathophysiologic mechanisms and biomarkers identified in CIDP.
La polyradiculoneuropathie inflammatoire démyélinisante chronique (PIDC) est une affection acquise, dysimmune, qui se caractérise par une grande hétérogénéité clinique, pronostique et de réponse thérapeutique. La physiopathologie et les cibles antigéniques impliquées sont encore incomplètement caractérisées. La recherche au cours des dernières décennies a permis la mise en évidence de l’implication de l’immunité cellulaire (lymphocytes T CD4+, CD8+ and macrophages), d’une rupture de la barrière hémato-nerveuse, d’une déficience de l’immunité régulatrice et de la présence d’altérations structurales au sein des nœuds de Ranvier et des paranœuds, possiblement médiées par des anticorps dirigés contre des molécules d’adhésion axogliales. Ces auto-anticorps perturberaient le regroupement des canaux sodiques et potassiques voltage-dépendants situés en regard des nœuds de Ranvier et des juxtaparanœuds, entraînant une altération de la conduction saltatoire et des blocs de conduction. L’objectif de cette revue est de faire le point sur les principaux mécanismes physiopathologiques et les biomarqueurs mis en évidence dans les PIDC.
Chronic inflammatory demyelinating polyneuropathy
2013, Journal of the Neurological Sciences
Citation Excerpt :
Autopsy studies have shown that the pathological changes are most pronounced in the spinal nerve roots, major plexuses and proximal nerve trunks [3,4]. More recently MRI studies show nerve hypertrophy and/or gadolinium enhancement in these same areas particularly in patients followed for long periods of time [5,6]. The reasons for the predilection of these areas to inflammatory processes in the inflammatory demyelinating neuropathies remain unknown.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the commonest treatable neuropathy in the western world. Untreated it may result in severe disability but if diagnosed and treated early there is effective treatment for the majority of patients. Typical CIDP is readily recognised but the diagnosis of other subgroups can be more challenging. The pathology of polyradiculoneuropathies such as CIDP characteristically affects the most proximal regions of the peripheral nervous system, nerve roots and major plexuses. It is important to test these regions with electrodiagnostic studies since routine neurophysiology may not encounter regions of pathology. Although accepted as an autoimmune disorder with an underlying immunopathology involving T cell and B cell responses, there is no agreement on major target antigens; however recent studies have highlighted a role for molecules in non compact myelin which play an essential role in the formation and maintenance of the nodal structures and hence in the function of ion channels central to saltatory conduction. Controlled trials have proven the efficacy of corticosteroid, intravenous immunoglobulin and plasma exchange in the short term and intravenous immunoglobulin also in the long term. Immunosuppressive agents are widely used but their efficacy has not been proven in controlled trials. Recent trials have shown the importance of attempting treatment withdrawal in patients apparently in remission to conserve treatments that are very expensive and in short supply, since a significant proportion of patients may enter long lasting remission following short term therapy. For the relatively small group of patients who do not respond to these first line therapies new agents including monoclonal antibodies may have a role.
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2010, Neuromuscular Disorders: Treatment and Management

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Chronic experimental allergic neuritis: An electrophysiological and histological study in the rabbit

Abstract

J. Neurol. Sci.

J. Neurol. Sci.

J. Neurol. Sci.

J. Neurol. Sci.

Effects of plasmapheresis on the course of experimental allergic neuritis

J. Neurol. Neurosurg. Psychiat.

Acute inflammatory demyelinating polyradiculoneuropathy

Spontaneous remission of autoimmune encephalomyelitis is inhibited by splenectomy, thymectomy or ageing

Nature

Chronic experimental allergic neuritis in the Lewis rat

J. Neuropathol. Exp. Neurol.

Chronic relapsing experimental allergic neuritis in Lewis rats

Effects of thymectomy and splenectomy

Acta Neuropathol. (Berl.)

Chronic inflammatory polyradiculoneuropathy

Conduction failure and nerve conduction slowing in experimental allergic neuritis induced by P2 specific T-cell lines

Ann. Neurol.

Experimentelle Untersuchungen zur Pathogenese der akut entzündlichen Polyneuritis

Dtsch. Med. Wochenschr.

Treatment of acute inflammatory poly-neuropathy

Ann. Neurol.

Conduction failure and nerve conduction slowing in experimental allergic neuritis induced by P₂ specific T-cell lines