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PubMed1998

Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination.

The new population of oligodendrocytes remyelinating an experimental demyelinating optic nerve lesion has been tracked backwards in time. Using autoradiography combined with electron microscopy and immunocytochemistry, serial sections of optic nerves from young adult cats were studied from 42 h (2 days) post-injection to 93 h (4 days) post-injection. The remyelinating oligodendrocyte lineage was found to commence with the single division of a resting progenitor cell residing in a central fascicular location outside the demyelinative lesion. The division of the founding progenitor cell occurs at 2 days post-lesion and results in two motile daughter cells. These cells, previously described by us as precursor cells, migrate to the lesion, closely appose demyelinated axons, produce axon wrapping processes and differentiate to become remyelinating oligodendrocytes. This study confirms that remyelinating oligodendrocytes originate from resting progenitor cells outside the lesion and not from mature oligodendrocytes, and implies that repeated demyelinative injury could exhaust the reparative capacity of such a region.

Animals↗
PubMed2004

MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood.

The prognostic factors for relapse of the initial MRI findings after a first episode of acute CNS inflammatory demyelination are unclear in children. In this study we aimed to identify initial MRI factors that are predictive of a second attack and disability after a first episode of acute CNS inflammatory demyelination in childhood. A cohort of 116 children who had a first episode of acute CNS inflammatory demyelination between 1990 and 2002 was studied using survival analysis methods. The initial MRI data were reviewed in a systematic, standardized, double-blind manner. The average follow-up was 4.9 +/- 3 years. Multivariate analysis showed that the rate of second attack was higher in patients with corpus callosum long axis perpendicular lesions (34 out of 116 patients, 30%) on the initial MRI [hazard ratio (HR) 2.89; 95% confidence interval (CI) 1.65-5.06] and/or with the sole presence of well-defined lesions (46 out of 116 patients, 40%) (HR 1.71; 95% CI 1.29-2.27). Both criteria were more specific predictors (100%) of relapse, demonstrating conversion to multiple sclerosis, than the three Barkhof criteria (63%), but were less sensitive (21% compared with 52%). None of the MRI criteria was predictive of severe disability. Using initial MRI and survival analysis methods, we identified two specific predictors of relapse and conversion to multiple sclerosis after a first episode of acute CNS inflammatory demyelination in childhood. Their low sensitivity, however, shows that this prediction remains difficult.

Acute Disease↗
PubMed1990

Inhibition of Theiler's virus-induced demyelination in vivo by tumor necrosis factor alpha.

Employing a murine model of multiple sclerosis which utilizes intracranial injection of Theiler's virus murine encephalomyelitis (TMEV) into SJL/J mice, we tested the potential role of tumor necrosis factor alpha (TNF-alpha) in ameliorating CNS demyelination. Infection with TMEV caused early grey matter inflammation (7 days post-infection) in the brain and spinal cord followed by chronic demyelination (35 days post-infection) in the spinal cord. Administration of recombinant human or mouse TNF-alpha starting 12 h prior to infection and then three times weekly had minimal effect on development of grey matter inflammation in the spinal cord. In contrast, TNF-alpha dramatically reduced demyelination present in spinal cord on days 14 and 35 after TMEV infection (P less than 0.01) when compared to controls. CNS virus titers of TMEV were not modified by TNF-alpha administration as measured on days 7, 14, and 35 following infection. In vivo administration of TNF-alpha inhibits TMEV-induced demyelination in susceptible SJL/J mice without affecting virus replication in the CNS.

Animals↗
PubMed2001

Dominance of autoreactive T cell-mediated delayed-type hypersensitivity or antibody-mediated demyelination results in distinct forms of experimental autoimmune neuritis in the Lewis rat.

The role of anti-myelin antibodies in the pathogenesis of experimental autoimmune neuritis (EAN) induced in the Lewis rat by immunization with peripheral nerve myelin has been assessed. Passive transfer with lymph node cells (LNC) or purified serum immunoglobulin from rats with EAN was employed to directly measure the contribution of B cells and anti-myelin antibodies to demyelination and disease. Lewis rats with EAN transferred by LNC or purified serum immunoglobulin from EAN donors in conjunction with a low dose of P2-specific CD4+ T cells demonstrated profound histopathological and neurophysiological evidence of demyelination during disease. In contrast, the classical adoptive transfer model of EAN in the Lewis rat induced by the injection of P2-specific CD4+ T cells was characterized by histopathological and neurophysiological evidence of axonal dysfunction and degeneration with limited demyelination. These findings demonstrate that the synergistic action of T cells and anti-myelin antibodies mediating demyelination or purely T cell mediated axonal dysfunction and degeneration are distinct pathways by which a specific autoimmune response in the peripheral nervous system can cause neurological disease.

Action Potentials↗
PubMed2002

Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease.

Certain human sera from patients with monoclonal gammopathies contain factors that induce myelin repair in animals with demyelinating disease. We hypothesize that antibodies functionally distinguish the serum of one patient from another. However, pooled normal polyclonal human IgM antibodies also induce remyelination. Definitive proof that specific antibodies are the biologically active components of serum is missing because unquestionably pure preparations of antibody molecules cannot be generated by fractionation. To demonstrate definitively that antibody is the biologically active component of patient serum, recombinant antibody was generated for evaluation in bioassays. The induction of remyelination in vivo requires milligram quantities of antibody. Consequently, an expression system was engineered to express high-titer, recombinant human IgM antibodies in vitro. A resulting recombinant antibody (rHIgM22) was evaluated for its ability to induce remyelination in the Theiler's virus mouse model of chronic-progressive demyelinating disease. We demonstrate that a single recombinant monoclonal antibody recapitulates the key characteristics of patient serum, including binding specificity, the induction of calcium signals in oligodendrocytes in vitro, and the induction of myelin repair within demyelinated plaques in vivo. The rHIgM22 antibody provides a new venue for the analysis of mechanisms governing remyelination and may prove useful in the treatment of demyelinating diseases.

Animals↗
PubMed1986

Peripheral nervous system demyelination with herpes simplex virus.

Inoculation of the cornea or footpad with herpes simplex virus Type I (HSV) has been shown to produce subsequent encephalitis or myelitis respectively. Although Schwann cells become infected, there is no destruction or demyelination in the peripheral nervous system (PNS). Demyelination only occurs in the central nervous system. Previous studies have shown that the Schwann cells infected with HSV do not produce enveloped viral particles. The studies presented here demonstrate that microinjection of HSV into the sciatic nerve of mice causes focal mononuclear cell infiltration and demyelination seven days after injection. The Schwann cells in this model produced enveloped virus. These studies demonstrate that when HSV is introduced into the extracellular space of the PNS, demyelination occurs.

Animals↗
PubMed1993

The potential for oligodendrocyte proliferation during demyelinating disease.

The potential for oligodendrocytes to proliferate in response to central nervous system injury was examined. We used intracerebral infection of Theiler's murine encephalomyelitis virus, a model for multiple sclerosis, which results in chronic demyelinating disease of SJL/J mice. Proliferating cells in spinal cord sections of adult mice were identified using simultaneous immunohistochemistry and in situ autoradiography ([3H]-thymidine incorporation). Seven different cell-specific markers were used to characterize proliferating cells as oligodendrocytes (myelin basic protein, proteolipid protein, galactocerebroside, CNPase), astrocytes (glial fibrillary acidic protein), microglia/macrophages (Griffonia simplicifolia isolectin B4) or T-lymphocytes (CD3). The average number of proliferating cells per area of spinal cord white matter was 11/mm2 in normal young adult mice compared to 61/mm2 in chronically infected mice. Most proliferating cells in normal spinal cord were not identified with these markers and were presumed to be progenitor glial cells. However, in spinal cord white matter of mice infected with Theiler's virus for approximately 4 months, 88% of proliferating cells were identified. Approximately one-third of all proliferating cells were in the oligodendrocyte lineage and expressed markers observed late in myelin differentiation. In demyelinated areas as compared to normal white matter, there was an 80- to 211-fold increase in the number of proliferating oligodendrocytes expressing myelin basic protein or proteolipid protein, respectively. The remainder of the proliferating cells in areas of demyelination were astrocytes, microglial cells and T-cells. These experiments support the hypothesis that factors within a demyelinating lesion promote the proliferation and differentiation of cells within the oligodendroglial lineage.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1995

MHC II expression in the CNS after long-term demyelination.

The ability of chronically demyelinated central nervous system (CNS) tissue to express major histocompatibility complex (MHC) class II molecules has been measured in mouse spinal cord cultures exposed for 1 and 3 weeks to demyelinating anti-white matter (WM) serum. From previous studies, it was known that after 3 weeks of demyelination in vitro, such cultures are incapable of remyelination. In the present report, MHC II levels were evaluated by immunocytochemistry and by Western and Northern blots. The results have shown that after both 1 and 3 weeks of exposure to myelinotoxic anti-WM serum, the cultures retained the ability to express MHC II and this could be further upregulated by incubation with interferon gamma (IFN gamma). Control groups showed increased expression of MHC II with age. By immunocytochemistry, all groups of cultures expressed high levels of MHC II and all groups showed upregulation after IFN gamma treatment. Anti-WM-treated cultures demonstrated slightly higher levels of MHC II than controls. Morphologically, the MHC II expression was associated with the surface of astrocytes. Semiquantitative analysis by Western blotting confirmed the increase in class II MHC expression in the long-term treated cultures after IFN gamma exposure, revealing no differences between anti-WM-treated and complement-treated cultures. This was also supported by Northern blotting which showed similar mRNA levels in both groups. These findings suggest that long-term demyelinated CNS tissue still possesses the ability to interact with CD4+ T cells, observations of significance to the expansion of the chronic multiple sclerosis lesion.

Animals↗
PubMed1999

Advances in chronic inflammatory demyelinating polyneuropathy: disease variants and inflammatory response mediators and modifiers.

Available data on the immunopathogenesis of chronic inflammatory demyelinating polyneuropathy remain still fragmentary and insufficient for a unified hypothesis. Macrophage-mediated demyelination appears to play a fundamental role and cytokines, especially tumour necrosis factor-alpha, participate in this process. The nature of antigen presenting cells, T-cell receptors, adhesion molecules between inflammatory cells and myelinated fibers and the apparent predominance of T helper cell 1-related cytokines need to be explored to design more specific immunotherapies. In chronic cases of chronic inflammatory demyelinating polyneuropathy, a concomitant axonal loss secondary to primary demyelination is common and should be taken into consideration in the design of future therapeutic strategies.

Antigens, Viral↗
PubMed2002

Acute demyelinating optic neuritis.

Acute demyelinating optic neuritis associated with multiple sclerosis (MS) is the most common cause of inflammation of the optic nerve. The Optic Neuritis Treatment Trial (ONTT) has provided important clinical data on the use of corticosteroids, and demonstrated that patients with characteristic inflammatory lesions within the brain on magnetic resonance imaging had a greater chance of developing clinically definite MS (CDMS). The current approach to patients with optic neuritis has been modified by the results of the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS). Patients with an initial clinical episode of demyelination (optic neuritis, incomplete transverse myelitis, or brain-stem/cerebellar syndrome) and at least two characteristic demyelinating lesions within the brain were randomized to receive interferon beta-1a or placebo after initial treatment with intravenous corticosteroids. At the 3-year point patients treated with interferon beta-1a showed a 50% less risk of CDMS. The results of this study have set the standard for patients with a first bout of demyelinating optic neuritis.

Acute Disease↗
PubMed2005

Spinal kyphosis causes demyelination and neuronal loss in the spinal cord: a new model of kyphotic deformity using juvenile Japanese small game fowls.

STUDY DESIGN: Histologic changes in the spinal cord caused by progressive spinal kyphosis were assessed using a new animal model. OBJECTIVES: To evaluate the effects of chronic compression associated with kyphotic deformity of the cervical spine on the spinal cord. SUMMARY OF BACKGROUND DATA: The spinal cord has remarkable ability to resist chronic compression, however, delayed paralysis is sometimes seen following the development of spinal kyphosis. In the past, no animal model to clarify the mechanism of spinal cord damage due to spinal kyphotic deformity has been available. METHODS: Laminectomy and bilateral facetectomy at the C4-C5 level was performed in 52 Japanese small game fowls. Histologic changes in the spinal cord associated with progressive kyphotic deformity were examined at different time points after surgery in each animal. The degree of spinal cord flattening and the severity of demyelination in histologic sections were quantitatively evaluated using an image analyzer, and their association with the kyphotic angle was analyzed. Changes in the microvascular distribution in the spinal cord were also examined by microangiography. RESULTS: In all operated animals, progressive kyphosis developed reproducibly. The kyphotic angle increased gradually until 3 weeks after surgery and stabilized thereafter. There was a significant correlation between the kyphotic angle and the degree of spinal cord flattening. The spinal cord was compressed most intensely at the apex of the kyphosis, where demyelination of the anterior funiculus as well as neuronal loss and atrophy of the anterior horn were observed. Demyelination progressed as the kyphotic deformity became more severe, initially affecting the anterior funiculus and later extending to the lateral and then the posterior funiculus. Angiography revealed a decrease of the vascular distribution at the ventral side of the compressed spinal cord. CONCLUSIONS: Progressive kyphosis of the cervical spine resulted in demyelination of nerve fibers in the funiculi and neuronal loss in the anterior horn due tochronic compression of the spinal cord. These histologic changes seem to be associated with both continuous mechanical compression and vascular changes in the spinal cord.

Animals↗
PubMed2006

MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis.

Theiler murine encephalomyelitis (TME) represents a highly relevant viral model for multiple sclerosis. Matrix metalloproteinases (MMPs) degrade extracellular matrix molecules and are involved in demyelination processes. To elucidate their impact on demyelination in TME, spinal cords of TME virus (TMEV)-infected SJL/J mice were taken at 9 different time points postinfection (pi) ranging from 1 hour to 196 days pi and investigated for the expression of TMEV, MMP-2, -3, -7, -9, -10, -11, -12, -13, -14, -15, -24, and TIMP-1 to -4 by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). High TMEV RNA levels were detectable throughout the observation period using RT-qPCR. In addition, TMEV RNA was visualized within demyelinated lesions by in situ hybridization. MMP-3 mRNA was significantly upregulated at 1 day pi and again in the late phase of infection. TIMP-1 mRNA was significantly elevated throughout the observation period. MMP-12 mRNA was most prominently upregulated in the late phase of infection and MMP-12 protein was localized in intralesional microglia/macrophages and astrocytes by immunohistochemistry. In summary, in early TMEV infection, MMP-3 and TIMP-1 mRNA upregulation might be directly virus-induced, whereas persistent TMEV infection directly or indirectly stimulated MMP-12 production in microglia/macrophages and astrocytes and might account for ongoing demyelination in TME.

Animals↗
PubMed2005

Glial grafting for demyelinating disease.

Remyelination of demyelinated central nervous system (CNS) axons is considered as a potential treatment for multiple sclerosis, and it has been achieved in experimental models of demyelination by transplantation of pro-myelinating cells. However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated remyelination since they were performed in conditions in which the chance for graft rejection was minimized. This article focuses on the factors determining survival of allogeneic oligodendrocyte lineage cells and their contribution to the remyelination of demyelinating CNS lesions. The immune status of the CNS as well as the suitability of different models of demyelination for graft rejection studies are discussed, and ways of enhancing allogeneic oligodendrocyte-mediated remyelination are presented. Finally, the effects of glial graft rejection on host remyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for myelin repair.

Central Nervous System↗
PubMed1990

Persistent infection of a glioma cell line generates a Theiler's virus variant which fails to induce demyelinating disease in SJL/J mice.

Theiler's murine encephalomyelitis virus (TMEV) induces demyelinating disease which is associated with persistent virus infection of the central nervous system. To study the interaction between TMEV and host cells, we infected the G26-20 glioma cell line in vitro, and this resulted in a lytic infection in which most, but not all, cells were killed. Surviving cells divided and formed a viable monolayer in which a small proportion of cells displayed viral cytopathic effects. Levels of virus produced by these cultures over a 6 month period fluctuated between 6 and 8 log10 p.f.u./ml as measured by viral plaque assay. Similarly, the percentage of cells producing both viral antigen and viral RNA, as measured by a simultaneous immunoperoxidase/in situ hybridization technique, varied between 5 and 30%. Although persistently infected cultures were susceptible to challenge by both vesicular stomatitis virus and herpes simplex virus, they were resistant to infection by homologous viruses. Interferon activity was not identified. TMEV isolated from passage 12 produced smaller plaques than wild-type Daniels strain virus (wt-DAV) on L-2 cell monolayers. In contrast to demyelination induced in SJL/J mice after intracerebral inoculation with wt-DAV, mice infected with the small plaque variant virus failed to develop viral persistence or chronic demyelination. However, following immunosuppression by total body irradiation, SJL/J mice infected with the small plaque variant developed viral persistence but no demyelination. Characterization of the biochemical and molecular determinants of the variant will lead to a better understanding of determinants important in viral persistence.

Animals↗
PubMed2003

Combination of high-dose intravenous immunoglobulins and itraconozole in treating chronic mycotic demyelinating optic neuritis.

Mycotic demyelinating optic neuritis is a neurological disorder of the visual system caused by mycotoxins released by indoor toxic molds. Although the health effect of indoor toxic mold on the population worldwide is now one of the "emerging diseases", its involvement in chronic demyelinating optic neuritis has not been reported. Most of the neurological and immunologic abnormalities associated with toxic mold mycotoxins are very difficult to treat successfully, especially neural demyelination of the central and peripheral nervous systems. This paper presents the case of a 42-year-old white female, in whom chronic demyelinating optic neuritis with persistent visual defects due to chronic exposure to toxic molds was diagnosed at the age of 34 years. In spite of all the therapeutic services given to her for over 8 years, her illness persisted and was difficult to treat. However, we successfully treated her with a combination of intravenous immune globulin (IVIG) and itraconozole (Sporanox) when all other treatment modalities failed. This is probably the first report where persistent toxic mold-induced neurological and immunologic disorders were successfully treated with a combination of itraconozole and IVIG.

Adult↗
PubMed1991

Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation.

The effects of decomplementation by cobra venom factor (CVF) on the pathogenesis of inflammation and demyelination in experimental allergic encephalomyelitis (EAE) and acute antibody-mediated demyelinating EAE (ADEAE) have been quantified histologically and immunocytochemically. In rats immunized with 50 micrograms of myelin basic protein in Freund's complete adjuvant containing 100 micrograms heat-killed Mycobacterium tuberculosis H37Ra, clinical signs of EAE were completely suppressed by two injections of CVF given 9 and 12 days post-immunization. Suppression of clinical disease was associated with a dramatic reduction in peri-vascular inflammation in the CNS, although immunohistochemical staining identified small numbers of infiltrating T cells and macrophages. In contrast, CVF treatment had no significant effect on the clinical severity of ADEAE and although C9 deposition within the CNS was virtually abolished, there was no statistically significant decrease in the extent of demyelination or inflammation. These observations indicate that in the absence of complement components C3 and C5 an antibody-dependent cell-mediated cytotoxic response plays an important role in the pathogenesis of antibody-mediated demyelination. The major role of the complement cascade in EAE appears to be the generation of pro-inflammatory factors that enhance the inflammatory response within the CNS in animals facing a mild encephalitogenic challenge.

Animals↗
PubMedDate not supplied

Observations on remyelination in the rabbit spinal cord following demyelination induced by lysolecithin.

The extent and type of remyelination that occurred following demyelination induced by intraspinal injection of small volumes of lysolecithin was examined in 24 rabbits. Unlike the rat and cat following this procedure remyelination is not complete even after 6 months' survival and little Schwann cell invasion occurs. The cellular environment around remyelinated and persistently demyelinated axons differed. Remyelination was associated with a good astrocytic presence and removal of myelin debris, while persistently demyelinated axons were surrounded by myelin debris and a poor astrocytic presence. It was conluded that the environment around the demyelinated axon influences oligodendrocyte remyelination.

Animals↗
PubMedDate not supplied

The effects of multiple sequential episodes of demyelination in the sciatic nerve of the mouse.

Intraneural injections of lysophosphatidyl choline were used to examine the effects of multiple episodes of demyelination and repair in the sciatic nerves of adult mice. It was found that the early phases of repair, from initiation of myelinolysis to the appearance of promyelinated fibres, were achieved more rapidly in multiple-injected nerves than in single-injected nerves. However, this lead was temporary, since subsequent remyelination was delayed in the multiple-injected nerves until several days after it had been established in most single-demyelinated nerves. Cell-mediated demyelination was seen in multiple-injected nerves, but never in single-injected nerves. The results are discussed in terms of a the contribution of supernumerary Schwann cells to the acute stage of the programme of cellular repair; and b the possibility that the 'normal' response to an injection of LPC in a nerve which has previously undergone several episodes of demyelination is exacerbated by a local and self-limiting immune-mediated reaction.

Animals↗