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PubMed1997

Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis.

Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis (Miller et al., 1994; J. Neurosci. 14: 6230-6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3-4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5-2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMkappa antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.

Animals↗
PubMed2004

Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients.

Most demyelinating forms of Charcot-Marie-Tooth type 1 (CMT1) neuropathy are slowly progressive and do not respond to anti-inflammatory treatment. In nerve biopsy samples, overt lymphocytic infiltration is absent, but pathological features typical of macrophage-related demyelination have been reported. In mouse models of CMT1, demyelination was substantially reduced when the mutants were backcrossed into an immunodeficient genetic background. A few individual patients with CMT1 respond to anti-inflammatory treatment; however, unlike most patients with CMT1, these patients show accelerated worsening of symptoms, inflammatory infiltrates in nerve biopsies, and clinical features resembling chronic inflammatory demyelinating polyneuropathy as well as CMT1. We conclude that in patients with typical CMT1 and in animal models, a cryptic and mild inflammatory process not responsive to standard anti-inflammatory treatment fosters genetically mediated demyelination.

Animals↗
PubMed2001

Spontaneous remyelination following extensive demyelination is associated with improved neurological function in a viral model of multiple sclerosis.

A major question in neurobiology is whether myelin repair can restore neurological function following the course of a severe, progressive CNS demyelinating disease that induces axonal loss. In this study we used Theiler's murine encephalomyelitis virus (TMEV) to induce a chronic progressive CNS demyelinating disease in mice that was immune-mediated and pathologically similar to human multiple sclerosis. Because immunosuppression of chronically TMEV-infected mice has been shown to enhance myelin repair, we first addressed the potential roles of CD4(+) and CD8(+) T cells in the inhibition of CNS remyelination during chronic disease. TMEV infection of susceptible PL/J mice deficient in CD4(+) but not CD8(+) T cells demonstrated a significant increase in severity of pathogenesis when compared with wild-type controls. This was characterized by enhanced demyelination, spinal cord atrophy, neurological deficits, and mortality. Interestingly, the PL/J CD4(-/-) mice that survived to the chronic stage of the disease had nearly complete spontaneous myelin repair mediated by both oligodendrocytes and infiltrating Schwann cells. Therefore, we next addressed whether this spontaneous myelin repair was associated with improved neurological function despite the increased pathology. Of interest, all surviving PL/J CD4(-/-) mice showed partial restoration of motor coordination and gait that coincided temporally with spontaneous myelin repair. Furthermore, functional recovery of motor coordination correlated strongly with the percentage of myelin repair mediated by Schwann cells, whereas restoration of hindlimb gait correlated with oligodendrocyte-mediated myelin repair. This is the first study to demonstrate that spontaneous remyelination correlates with partial restoration of neurological function during the course of a progressive, immune-mediated CNS demyelinating disease. Of greater importance, functional recovery occurred despite previous severe demyelination and spinal cord atrophy.

Animals↗
PubMed2002

Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation.

Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin protein, proteolipid protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N-acetyl aspartate (NAA), a marker of axonal integrity. Length-dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1-deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients' brain tissue also demonstrated a length-dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin protein PLP1. This degeneration is length-dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1-mediated axonal--glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.

Adult↗
PubMed2002

Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10.

Inflammatory cell recruitment is an important step in the pathogenesis of autoimmune demyelinating diseases of the PNS. Chemokines might play a critical role in promoting leucocyte entry into the nervous system during immune-mediated inflammation. Here, we report the expression pattern of the chemokine receptors CCR-1, CCR-2, CCR-4, CCR-5 and CXCR-3 in sural nerve biopsies obtained from patients with classical Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy and various non-inflammatory neuropathies. A consistent chemokine receptor expression pattern was immunohistochemically detected in inflammatory demyelinating neuropathies and quantitation of labelled mononuclear cells revealed significantly elevated cell counts compared with controls. CCR-1 and CCR-5 were primarily expressed by endoneurial macrophages, whereas CCR-2, CCR-4 and CXCR-3 could be localized to invading T lymphocytes. Quantitative analysis revealed that CXCR-3 was expressed at highest numbers by infiltrating T cells compared with the other receptors. Thus, expression and distribution of CXCR-3 suggest a specific role of this receptor in chemokine-mediated lymphocyte traffic into the inflamed PNS tissue. Therefore, we further analysed the expression of its ligands interferon-gamma-inducible protein of 10 kDa (IP-10) and monokine induced by interferon-gamma (Mig). Significantly increased levels of IP-10 could be measured in the CSF of patients with inflammatory neuropathies, whereas no differences were observable for Mig. In situ hybridization for IP-10 mRNA mirrored the distribution of the cognate receptor within the inflamed PNS, and delineated endothelial cells as the primary cellular source of IP-10. Our results imply a pathogenic role for specific chemokine receptors and IP-10 in the genesis of inflammatory demyelinating neuropathies.

Adult↗
PubMed2004

Clinicopathological and genetic study of early-onset demyelinating neuropathy.

Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene.

Adolescent↗
PubMed2006

A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination.

Recent studies have revealed widespread demyelination in the cortex of patients with chronic multiple sclerosis. In contrast to white matter lesions, cortical multiple sclerosis lesions are accompanied by only minor inflammation. Research into the pathogenesis of cortical lesion formation has been hampered by the fact that the conventional rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), does not regularly affect the cortex. To overcome this limitation we developed a new rat model of cortical multiple sclerosis. Lesions were stereotactically targeted to the cerebral cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with myelin oligodendrocyte glycoprotein (MOG). We thus generated highly reproducible demyelinated lesions in the neocortex with remarkable histological similarities to cortical multiple sclerosis lesions. The focal cortical EAE model led to the typical pattern of intracortical and subpial demyelination, infiltration with inflammatory cells, complement deposition, acute axonal damage and neuronal cell death. Surprisingly, extensive cortical inflammation largely resolved within 2 weeks. Furthermore, cortical demyelination was readily compensated by rapid remyelination. Our data thus suggest that cortical inflammation is a transient phenomenon, and that remyelination of cortical inflammatory-demyelinating lesions may occur rapidly.

Animals↗
PubMed2005

Repopulation of oligodendrocyte progenitor cell-depleted tissue in a model of chronic demyelination.

Some, but not all, chronically demyelinated multiple sclerosis (MS) lesions are depleted of oligodendrocyte progenitor cells (OPCs) suggesting that OPCs are destroyed during the process of demyelination and some factor impedes OPC repopulation of the depleted tissue. The chronically demyelinated axons in MS lie in an astrocytic environment and it has been proposed that this might impede entry of OPCs into such regions. By depleting a short length of spinal cord of its OPCs using 40 Gy of X-irradiation in both normal rats and rats with progressive myelin loss accompanied by an astrocytosis (taiep rats), we investigated whether such changes affect the ability of OPCs to repopulate OPC-depleted tissue. In both taiep and normal rats, the rate of repopulation decreases with age, but no difference was detected in the rate at which OPCs repopulated normally myelinated and chronically demyelinated and astrocytosed tissue. This indicates that, if the astrocytic environment of the taiep central nervous system (CNS) is comparable to that found in MS lesions, then the presence of chronically demyelinated axons and astrocytosis in chronic MS lesions does not represent a barrier to repopulation of the tissue by OPCs. However, similar to the situation in the normal adult rodent CNS, the rate of repopulation by endogenous OPCs in aged taiep rats is very slow, approximately 0.2 mm per week.

Age Factors↗
PubMed1985

Preliminary analysis of cell and serum-induced demyelination in vitro using a syngeneic system.

Previous studies on immune-mediated demyelination in vitro have usually tested sera and lymphoid cells in heterologous systems. The present study involved the examination of CNS cultures of SJL/J mouse spinal cord exposed to sera and lymphoid cells isolated from animals of the same strain previously injected with syngeneic spinal cord homogenate (SSCH) to induce acute experimental autoimmune encephalomyelitis (EAE). Examination of treated versus control cultures by light and electron microscopy at varying time points after exposure showed that spleen cells from animals with EAE produced significant demyelination and oligodendroglial cell destruction. Lymph node cells and sera from the same animals showed the same type of demyelination without marked oligodendroglial cell damage. The degree of myelin damage induced by spleen cells and sera did not correlate with the clinical status of the animal but a slight positive correlation was noted with lymph node cells. Cells and sera from control animals did not induce significant demyelination. These results suggest that in this syngeneic mouse system, there was a differential effect among cells from spleens and lymph nodes, and serum. This syngeneic system might allow for more meaningful pathologic and genetic analyses of immune-mediated demyelination.

Animals↗
PubMed1988

Autoimmune demyelination in the central nervous system.

Autoimmune demyelination was studied in EAE induced by active challenge or by transfer of effector T-cell lines or clones specific for myelin basic protein or proteolipid apoprotein. The following points became clear: (1) Proteolipid apoprotein is responsible for widespread demyelination; (2) demyelination is more significant in EAE with a more chronic disease process; (3) a single T-cell clone can mediate significant demyelination without the aid of recipient-derived T-cell populations; (4) the difference in vulnerability between axons and myelin may account for the T-cell-mediated demyelination; and (5) effector T-cell clones can be activated by allogeneic antigens.

Animals↗
PubMed1981

The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.

1. 4-Aminopyridine (4AP) and tetraethylammonium ions (TEA), which block voltage-dependent potassium channels in other nerve membranes, have been used to study nerve conduction in fibres of normal rat spinal roots and those demyelinated with diphtheria toxin. The pharmacological actions have been compared with those of temperature. 2. Both TEA and 4AP increased the amplitude and duration of the monophasically recorded compound action potentials of non-myelinated fibres in normal rat dorsal roots. Enhancement of the action potential amplitude by 4AP was maximal near 1 mM, and was not readily reversed by washing. At concentrations up to 50 mM the action of TEA was weaker and reversible. 3. In normal dorsal and ventral roots TEA (20 mM) and 4AP (5 mM) had only a mildly depressant action on the compound action potentials of myelinated fibres. Whereas the slight reduction in peak amplitude and increase in width was also found in a single fibres treated with TEA, none was discerned in single fibres exposed to 4AP over a wide temperature range. 4. It is concluded that voltage-dependent potassium channels occur in significant numbers in mammalian non-myelinated fibres, but not at nodes of Ranvier. 5. Spinal roots previously treated with diphtheria toxin to cause demyelination were studied by longitudinal current analysis. Fibres affected by diphtheria toxin had a late phase of outward current, either restricted to nodes or, in the case of continuous conduction, distributed along internodes, and this outward current was specifically blocked by 4AP. 6. Both 4AP and TEA increased the temperature at which conduction block occurred in most single demyelinated fibres, so that in some cases fibres blocked at physiological temperatures were enabled to conduct. 4AP was more potent than TEA, but less consistent in its effect. 7. It is concluded that potassium channels are present at widened nodes and in internodal axolemma exposed by demyelination. Their presence enables TEA and 4AP to overcome conduction block in some demyelinated nerve fibres.

4-Aminopyridine↗
PubMed1988

Antibody to myelin-associated glycoprotein produces central nervous system demyelination.

Antibodies to myelin-associated glycoprotein (MAG) have been implicated in certain human demyelinating diseases of the peripheral nervous system. In the present study, a monoclonal antibody to MAG with 20% guinea pig serum (GPS) was injected into mammalian optic nerves and produced in vivo demyelination associated with three ultrastructural patterns of myelin injury: (1) widened lamellae; (2) myelin vesiculation; and (3) cell-associated myelin damage. These patterns of myelin injury have been observed neuropathologically in MS and in a demyelinating peripheral neuropathy associated with plasma cell dyscrasias. Demyelination was not observed in nerves injected with anti-MAG and heated GPS or a monoclonal antibody to chick myoblasts and 20% GPS. These results establish the ability of anti-MAG to produce in vivo demyelination of mammalian CNS and indicate that a single antibody directed against a specific myelin component may initiate multiple types of myelin damage.

Animals↗
PubMed1987

Demyelination induced by T cell lines and clones specific for myelin basic protein in mice.

Neuropathological studies were performed in order to investigate experimental allergic encephalomyelitis induced by long-term cultured T cell lines and clones specific for myelin basic protein, which were established from SJL/J and DDD/1 mice. All antigen-activated T line or clone cells induced similar disease in euthymic and athymic mice with a common I-A haplotype. The lesion was characterized by perivascular and parenchymal infiltration of mononuclear cells with abundant polymorphonuclear cells located mainly in the lower spinal cord. Axons were severely affected and decreased in number. However, demyelination was present in all cases and was especially marked when recipient mice were: given whole-body X-ray irradiation, I-A compatible other strains, or were congenitally athymic. Topographically, demyelinated axons were most prominent in the root exit and entry zones of the lower spinal cord. Repeated transfer or relapse did not seem to be the factor responsible for enhancing demyelination. We conclude that: inflammation with axonal damage is the main feature of murine experimental allergic encephalomyelitis induced by myelin basic protein-specific T cell lines and clones, demyelination definitely occurs under certain conditions and in certain areas especially at the root exit and entry zones in nude mice, and a single T cell clone induces experimental allergic encephalomyelitis lesions associated with demyelination without the aid of interaction with another recipient-derived T cell population.

Animals↗
PubMed1982

Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection.

Mice experimentally infected with Theiler's murine encephalomyelitis virus (TMEV) develop a persistent infection of the central nervous system (CNS). The most striking feature of this infection is the occurrence of inflammatory primary demyelination in the spinal cord white matter. The pathogenesis of myelin degeneration in this model has not been clarified, but morphologic and immunologic data suggest that the host immune response plays a major role in the production of myelin injury. Because of low virus titers in infected adult mice and of the small size of TMEV, virus particles have never been observed in this demyelinating model. Yet elucidation of the types of cells in the CNS supporting virus replication would be important for a better understanding of both virus persistence and virus-induced demyelinating pathology. The present paper is a sequential study of the localization of TMEV in the spinal cord in infected mice by ultrastructural immunohistochemical techniques. Results indicate that virus replication is mainly in neurons during the acute phase of the disease, while in the chronic phase viral inclusions are mainly found in macrophages in and around demyelinating lesions. Other cells are also infected, but to a lesser degree. In the neuronal system both axoplasmic and dendritic flow appear to facilitate the spread of virus in the CNS. In macrophages, the presence of virus particles and the association of virus with altered components of the cytoskeleton support active virus production rather than simple internalization. The macrophage appears to play an important role in both the establishment of virus persistence and in the process of demyelination in this animal model.

Animals↗
PubMed1980

A new pattern of spinal-cord demyelination in guinea pigs with acute experimental allergic encephalomyelitis mimicking multiple sclerosis.

A technique is described for producing large demyelinating lesions of the spinal cord in the guinea pig. Guinea pigs were pretreated by immunization with ovalbumin and water-soluble adjuvant (N-acetyl-muramyl L-alanyl D-isoglutamine, MDP) in water-in-oil emulsion (Freund's incomplete adjuvant). They were given a large dose (10 mg) of ovalbumin i.p. one month later. After a few weeks the animals were sensitized with guinea-pig basic protein in Freund's complete adjuvant. Five out of 11 animals developed large, distinctive, sharply demarcated, symmetrical demyelinating lesions within 30 days. These lesions occurred in the dorsal and anterior columns, root entry zones and subpial region of the spinal cord. Histology showed a considerable amount of free lipids. There were also infiltrative lesions of classical experimental allergic encephalomyelitis (EAE) of normal severity in the same animals. The demyelinating lesions resembled those seen in multiple sclerosis in their location and extent in the spinal cord and in the presence of free lipids. Control experiments indicated that pretreatment with ovalbumin/MDP and the second injection of ovalbumin was necessary for all the demyelination; moreover guinea pigs immunized with basic protein in Freund's complete adjuvant or Freund's incomplete adjuvant plus MDP without pretreatment only developed classical EAE with minimal or no demyelination.

Adjuvants, Immunologic↗
PubMed2004

Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy.

Electrodiagnosis plays an important role in the early detection and characterization of inflammatory demyelinating polyradiculoneuropathies, because timely treatment reduces morbidity and disability. The challenge consists of defining electrodiagnostic criteria that are highly specific for primary demyelination but sufficiently sensitive to be useful in clinical practice. We compared 10 published sets of criteria in 53 patients with demyelinating Guillain-Barré syndrome (GBS) and 28 with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Specificity of criteria sets was tested in 40 patients with amyotrophic lateral sclerosis (ALS) and 32 with diabetic polyneuropathy (DPN). Sensitivity ranged from 24 to 83% (mean, 54.3%) in GBS and 39 to 89% (mean, 64.9%) in CIDP. With regard to ALS, specificity was 100% for nine sets but was 97% in one. In contrast, 3-66% of DPN patients fulfilled criteria in eight of ten sets. We propose a set of criteria with 72% and 75% sensitivity in our GBS and CIDP patient series, respectively, and 100% specificity with regard to ALS and DPN. Our data illustrate that most, but not all, patients can be electrodiagnostically ascertained.

Adolescent↗
PubMed1964

THE APPLICATION OF TISSUE CULTURE TO THE STUDY OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS. II. SERUM FACTORS RESPONSIBLE FOR DEMYELINATION.

1. In the presence of a source of complement, the gamma 2 globulin fraction of rabbit EAE serum results in complete demyelination of myelinated cultures of rat cerebellum. Exposure of the serum to homologous or heterologous brain specifically removes the myelinotoxic activity whereas exposure to non-nervous tissue does not. Polylysine has no effect upon the cultures or upon the demyelinative potency of EAE, whereas heparin inhibits activity presumably through an effect on complement. 2. With the fluorescent antibody technique, the EAE globulins are specifically localized to the myelin sheaths and glial cell membranes during the process of demyelination. As demyelination proceeds, the globulins become localized within the neuroglia in a homogeneous manner which contrasts sharply with the punctate pattern observed in control experiments. 3. The "delayed sensitivity" and classical antibody interpretations of experimental allergic encephalomyelitis are discussed. It is suggested that several factors may be responsible for the pathogenesis of EAE, one of which may well be a myelinotoxic antibody.

Animals↗
PubMed1975

Mouse hepatitis virus-induced recurrent demyelination. A preliminary report.

Four-week-old BALB/c mice inoculated intracerebrally with the JHM strain of mouse hepatitis virus developed an acute demyelinating disease followed by apparent recovery with remyelination. When surviving mice were examined 16 months later, small areas of active demyelination were still present. This is the first reported example, to our knowledge, of an experimental viral infection in which acute demyelination with recovery is followed by persisting or recurring demyelination.

Animals↗