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PubMed1991

Treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulin.

Chronic inflammatory demyelinating polyneuropathy is an immune-mediated demyelinating peripheral neuropathy usually treated with immunosuppressants. We reviewed our experience treating 15 patients (9 men, 6 women) with intravenous immunoglobulin. Six patients were on other therapies at the time of intravenous immunoglobulin infusions (4, prednisone; 2, prednisone and azathioprine). The dose of intravenous immunoglobulin was either 0.3 or 0.4 gm/kg/day for 4 to 5 days. Transient fever occurred in 1 patient. Subjective improvement in sensory symptoms was reported by almost all patients. Objective improvements in strength or functional tasks occurred in only 3 patients, a man with human immunodeficiency virus infection, a 14-year-old girl, and a woman with an immunoglobulin G kappa paraprotein. Our results suggest that individual patients may respond to intravenous immunoglobulin therapy. A multicenter controlled trial is needed to assess properly the role of intravenous immunoglobulin therapy in patients with chronic inflammatory demyelinating polyneuropathy.

Adolescent↗
PubMed1991

Presence of the terminal complement complex (C5b-9) precedes myelin degradation in immune-mediated demyelination of the rat peripheral nervous system.

In this study, the terminal complement complex C5b-9 (TCC) was localized by immunocytochemistry at different clinical stages of experimental autoimmune neuritis. Deposits of TCC were found on the surface of Schwann cells and their myelin sheaths, and to some extent in the extracellular space at predilective sites of impending demyelination before onset of clinical signs and for a short period thereafter. Additionally, TCC was deposited on the surface of W3/13 positive leukocytes. No TCC immunoreactivity was seen in the distal stump of transected sciatic nerves 1 to 15 days after axotomy. The early and transient deposition of TCC on Schwann cells and myelin sheaths in experimental autoimmune neuritis before overt demyelination suggests that complement activation plays a pathogenic role in the initiation of immune-mediated myelin damage. The lack of TCC immunoreactivity after nerve transection excludes a nonspecific activation process. The signals involved in local TCC formation in demyelinating peripheral nervous system disorders have yet to be explored.

Animals↗
PubMed1992

Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques.

We used proton magnetic resonance (MR) spectroscopic imaging to determine the serial changes in MR signals from choline, creatine, lactate, and N-acetylaspartate in and around a large demyelinating lesion followed over a period of 8 months. Elevated lactate and choline signals were observed at the first examination 3 days after the onset of symptoms. Reduced N-acetylaspartate signals were observed a few days afterward. The abnormal metabolite signals varied in different regions of the lesion and extended beyond the borders of abnormal signal intensity seen on conventional MR imaging (MRI). On the last examination at 8 months when the lesion appeared much smaller on MRI, choline signals from the center of the lesion were still high, but were falling. Choline signals outside the lesion on MRI had returned to normal as had lactate signals everywhere. Importantly, there was no recovery of N-acetylaspartate signals in or adjacent to the lesion on MRI. This serial study demonstrates the potential of MR spectroscopic imaging for characterizing the chemical pathological evolution of demyelinating lesions in ways that conventional MRI cannot. We propose that abnormal signals from choline can indicate recent regional demyelination, while persistent abnormal signals from N-acetylaspartate can provide an index of irreversible damage in the nervous system.

Acute Disease↗
PubMed1998

In vivo differentiation of astrocytic brain tumors and isolated demyelinating lesions of the type seen in multiple sclerosis using 1H magnetic resonance spectroscopic imaging.

We used computer pattern recognition of proton magnetic resonance spectroscopic image data to differentiate between brain tumors and large, isolated, demyelinating lesions of the type seen in multiple sclerosis. Leave-one-out linear discriminant analyses correctly classified resonance profiles from five acute demyelinating lesions, 20 low-grade astrocytomas, 22 anoplastic astrocytomas, and 24 glioblastomas. Classification of nonacute lesions will require further development, as the metabolic profiles of demyelinating lesions evolve over time.

Adult↗
PubMed2006

Initial capsid-specific CD4(+) T cell responses protect against Theiler's murine encephalomyelitisvirus-induced demyelinating disease.

Central nervous system (CNS) infection by Theiler's murine encephalomyelitis virus (TMEV) causes an immune-mediated demyelinating disease similar to human multiple sclerosis in susceptible mice. To understand the pathogenic mechanisms, we analyzed the level, specificity, and function of CD4(+) Th cells in susceptible SJL/J and resistant C57BL/6 mice. Compared to resistant mice, susceptible mice have three- to fourfold higher levels of overall CNS-infiltrating CD4(+) T cells during acute infection. CD4(+) T cells in the CNS of both strains display various activation markers and produce high levels of IFN-gamma upon stimulation with anti-CD3 antibody. However, susceptible mice display significantly fewer (tenfold) IFN-gamma-producing Th1 cells specific for viral capsid epitopes as compared to resistant mice. Furthermore, preimmunization with capsid-epitope peptides significantly increased capsid-specific CD4(+) T cells in the CNS during the early stages of viral infection and delayed the development of demyelinating disease in SJL/J mice. This suggests a protective role of capsid-reactive Th cells during early viral infection. Therefore, a low level of the protective Th1 response to viral capsid proteins, in conjunction with Th1 responses to unknown epitopes may delay viral clearance in susceptible mice leading to pathogenesis of demyelination during acute infection, as compared to resistant mice.

Acute Disease↗
PubMed2003

Lentiviral vectors for gene delivery to normal and demyelinated white matter.

Lentiviral vectors are increasingly used for gene delivery to neurons and in experimental models of neurodegeneration. Their use in gene delivery to white matter and their potential value in preventing or repairing CNS demyelination has received less attention. Here we show using a VSV-G-pseudotyped HIV-derived vector expressing the marker gene LacZ that lentiviral vectors transduce the major macroglial cell types present in normal white matter (astrocytes, oligodendrocytes, and oligodendrocyte progenitors). Injection of lentiviral vectors causes an inflammatory response at the injection site characterized by OX42(+) and ED1(+) macrophages, but only a few CD8(+) and no CD4(+) lymphocytes, and mild demyelination. Injection of lentiviral vectors into areas of toxin-induced demyelination resulted in significant numbers of cells expressing the marker gene and was a more effective means of gene delivery than was a LacZ-expressing murine retroviral vector.

Animals↗
PubMed2004

Expression of the low-affinity neurotrophin receptor, p75(NTR), is upregulated by oligodendroglial progenitors adjacent to the subventricular zone in response to demyelination.

Precursor cells have the capacity to repopulate the demyelinated brain, but the molecular mechanisms that facilitate their recruitment are largely unknown. The low-affinity neurotrophin receptor, p75(NTR), may be one of these regulators; however, its expression profile by oligodendroglia within the multiple sclerosis (MS) brain remains uncertain. We therefore assessed the expression profile of this receptor within 8 MS and 4 control brains. We found no evidence of expression of p75(NTR) by mature oligodendrocytes. Instead, we demonstrated the presence of p75(NTR) on a subgroup of NG2-positive oligodendroglial progenitors in a periventricular plaque in one MS sample. Notably, p75(NTR)-expressing cells were also detected within the subventricular zone (SVZ) of this brain, adjacent to the periventricular plaque. In animals with experimental demyelination we observed similar patterns of p75(NTR) expression, initially confined to precursor cells within the SVZ, followed at later stages in the disease course by its expression amongst a subset of oligodendroglial progenitors within the corpus callosum. These data suggest that a population of precursor cells within the SVZ can be induced to express p75(NTR) and to subsequently assume an oligodendroglial progenitor phenotype in response to demyelination in the adjacent white matter.

Adult↗
PubMed2006

Haplotype matching is not an essential requirement to achieve remyelination of demyelinating CNS lesions.

Transplantation of oligodendrocyte precursor cells (OPCs) results in efficient remyelination in animal models of demyelination. However, the experiments so far undertaken have not addressed the need for tissue-type matching to achieve graft-mediated remyelination. Examination of MHC expression (main determinant of allograft rejection) by OPCs showed nondetectable levels under standard culture conditions and upregulation of MHC Class I expression only upon exposure to interferon gamma. We therefore hypothesized that MHC matching of OPC grafts may not be crucial to achieve transplant-mediated remyelination. Transplant experiments performed using a nonself repairing toxin-induced demyelination model showed that, similarly to allogeneic neurons, survival of allogeneic oligodendrocyte lineage cells is influenced by donor-host haplotype combination and graft composition. Transplantation of allogeneic mixed glial cell cultures resulted in remyelination failure by 1 month postengraftment due to a rejection response targeting both myelinating oligodendrocytes and OPCs, suggesting that inflammation-induced upregulation of OPC MHC I expression results in susceptibility to cytotoxic T cell attack. In contrast, remyelination persisted for at least 2 months following transplantation of OPC-enriched cultures whose overall MHC expression level was significantly decreased. While OPC-enriched preparations elicited delayed type hypersensitivity responses in hosts sensitized to alloantigens, allografting of such preparations into a central nervous system demyelinating lesion did not result in recipient priming. We conclude that while allografted oligodendrocyte lineage cells become targets of a graft rejection response once this response has been initiated, transplantation of OPC-enriched preparations can evade priming against alloantigens and graft rejection. This finding indicates that close tissue matching may not be an essential requirement for successful transplant-mediated remyelination.

Animals↗
PubMed2001

Axonal degeneration is an early pathological feature in autoimmune-mediated demyelination in mice.

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS), characterised by focal destruction of myelin. Although it is evident that the immune system contributes to tissue destruction in MS, it is still unclear as to whether this immune response is a cause or a consequence of the disease process. In addition, there is debate over the contribution of axonal damage to clinical progression. We have described a murine model of relapsing-remitting MS (RR-MS), the most common form of the disease, following immunisation with the myelin component, myelin oligodendrocyte glycoprotein (MOG). We showed that a single injection of a MOG peptide (MOG(35-55)) in NOD/Lt mice induces a paralytic relapsing disease with extensive plaque-like demyelination. This model also mimics many of the immunological features associated with RR-MS. To investigate the relationship between clinical episodes, inflammation, and demyelination/remyelination, we analysed lesions during each attack and remission over the course of the disease, using histological, immunocytochemical, and electron microscopy (EM) techniques. We show that morphological features of lesions in our model resemble those observed in MS. Indeed, severe inflammation and demyelination coincide with the peak of clinical episodes while remissions are characterised by quiescent plaques. Furthermore, axonal damage is evident from the earliest stage of the disease and increases in severity with subsequent relapses. These data establish that in the model of MS-like disease, the peak of clinical episodes coincides with severe inflammation and demyelination and that axonal pathology correlates with clinical progression.

Animals↗
PubMed2002

Progenitor cells derived from the adult human subcortical white matter disperse and differentiate as oligodendrocytes within demyelinated lesions of the rat brain.

A distinct population of white matter progenitor cells (WMPCs), competent but not committed to generate oligodendrocytes, remains ubiquitous in the adult human subcortical white matter. These cells are present in both sexes and into senescence and may constitute as much as 4% of the cells of adult human capsular white matter. Transduction of adult human white matter dissociates with plasmids bearing early oligodendrocytic promoters driving fluorescent reporters permits the separation of these cells at high yield and purity, as does separation based on their expression of A2B5 immunoreactivity. Isolates of these cells survive xenograft to lysolecithin-demyelinated brain and migrate rapidly to infiltrate these lesions, without extending into normal white matter. Within several weeks, implanted progenitors mature as oligodendrocytes, and develop myelin-associated antigens. Lentiviral tagging with green fluorescent protein confirmed that A2B5-sorted progenitors develop myelin basic protein expression within regions of demyelination and that they fail to migrate when implanted into normal brain. Adult human white matter progenitor cells can thus disperse widely through regions of experimental demyelination and are able to differentiate as myelinating oligodendrocytes. This being the case, they may constitute appropriate vectors for cell-based remyelination strategies.

Adult↗
PubMed2005

Effects of the major histocompatibility complex loci and T-cell receptor beta-chain repertoire on Theiler's virus-induced demyelinating disease.

We have investigated the potential effects of H-2 and T-cell receptor (TCR) V beta family genes on induction of T-cell immunity and susceptibility to virally induced demyelinating disease by using BALB.S (H-2K(s)A(s)D(s)) and BALB.S 3 R (H-2K(s)A(s)D(d)/L(d)) mice. These parameters were compared with those of highly susceptible SJL/J (H-2K(s)A(s)D(s)) mice that contain only one-half of TCR V beta family genes compared with the above-mentioned strains. Our results demonstrate that BALB.S but not BALB.S 3 R mice are susceptible similar to SJL/J mice. Although the level of CD4(+) T-cell infiltration to the CNS was elevated in susceptible mice, virus-specific immune responses restricted with H-2(s) were similar in these mice. No preferential use of V beta families associated with differences in the major histocompatibility complex (MHC) components was apparent. However, the pattern and sequence of CDR 3 distribution shows T-cell clonal accumulation in the CNS associated with the H-2 components. Further anti-CD8 antibody treatment of resistant BALB.S 3 R mice abrogated resistance to demyelinating disease, indicating that CD8(+) T cells restricted with H-2D(d)/L(d) are most likely to exert resistance in BALB.S 3 R mice. These studies indicated that TCR V beta and MHC class II genes are the secondary to a particular MHC class I gene expression in susceptibility to virally induced demyelinating disease.

Animals↗
PubMed2006

Electrophysiological abnormalities precede apparent histological demyelination in the central nervous system of mice overexpressing proteolipid protein.

Myelin proteolipid protein (plp), a major myelin protein in the CNS, has been proposed to function in myelin assembly. Transgenic mice overexpressing the plp gene by introduction of two extra wild-type (Wt) mouse plp genes (plp(tg/-)) exhibit normal myelination and ion channel clustering at the age of 2 months. However, at the age of 5 months, demyelination becomes observable, accompanied by a reduction in the number of K+ channel clusters at Ranvier's node and a progressive increase in motor deficit. To clarify how these age-dependent changes are related to nerve conduction in the CNS, we analyzed the conduction velocity (CV) and relative refractory period (RRP) of identified spinal ascending or descending tracts, such as the dorsal column pathway, the vestibulospinal and reticulospinal tracts, and the pyramidal tract, in plp(tg/-) mice 2, 5, and 8 months of age. We found that CVs decreased as age increased. Importantly, CVs were significantly reduced and prolonged RRPs were observed in 2-month-old (2M) plp(tg/-) mice that had no apparent demyelination. Immunohistological examination revealed that densities of Na+ and K+ channel clusters decreased as plp(tg/-) and Wt mice aged. However, a clear correlation was not observed between CVs and mean channel cluster densities or between mean channel cluster densities and progress of demyelination. Performance in the rotarod test was normal in 2M plp(tg/-) mice but deteriorated in mice older than age 5 months. These results suggest that electrophysiological analysis can detect the abnormalities of the plp(tg/-) mice earlier than histological or behavioral measures.

Animals↗
PubMed1986

In vitro cytotoxicity and demyelination induced by Theiler viruses in cultures of spinal cord slices.

The cytopathic effects caused by Theiler viruses to myelinated organotypic spinal cord cultures was studied by light and electron microscopy. Heavily myelinated cultures, 2-3 weeks in vitro were infected with WW and GD VII viruses. Mock infection served as control. On light microscopy cytopathic effects and demyelination became evident about 16-17 hr after infection. Demyelination observed in WW virus-infected cultures was much more pronounced than in cultures infected with GD VII viruses. The myelin in mock-infected cultures remained undamaged. Electron microscopy revealed that in control cultures cells were intact, exhibiting numerous synapses and a network of axons enwrapped by multilayered myelin sheaths. Virus-infected spinal cord slices showed that a more severe cytotoxicity was caused by GD VII virus than by WW virus. The cytopathology included accumulation of cytoplasmatic vacuoles, margination of chromatin, synapse and cell disintegration, and various degrees of demyelination. Several GD VII virions were observed, arranged in crystalline arrays, mainly in electron-opaque cells, but not within axons. WW virions on the other hand were only occasionally encountered.

Animals↗
PubMed1992

Endogenous aFGF expression and cellular changes after a demyelinating lesion in the spinal cord of adult normal mice: immunohistochemical study.

Fibroblast growth factors (FGFs) are known to act on glial cells in vitro. At the present time, their involvement in the remyelinating process of the adult central nervous system (CNS) is still unknown. In the present study, using immunohistochemistry (IHC), we investigated the evolution in time and space of acidic FGF (aFGF) expression and CNS cell changes occurring after a chemically induced demyelinating lesion. In a first early period, aFGF immunostaining was shown to decrease around the demyelinated area. A dramatic increase was then observed and was accompanied by an increase of cell density around and inside the lesion. This was correlated with the beginning of remyelination. Late after demyelination, while remyelination was still in progress, aFGF immunostaining of the lesion and unlesioned spinal cord were comparable. A role of aFGF in remyelination is proposed.

Animals↗
PubMed1995

Morphological and molecular response of the MOCH-1 oligodendrocyte cell line to serum and interferon-gamma: possible implications for demyelinating disorders.

The regional loss of oligodendrocytes is thought to be an important pathological event in a variety of demyelinating diseases of the central nervous system (CNS). Various components of serum, which are normally excluded from the CNS by the blood-brain barrier, have been implicated as mediators of demyelinating disorders. We have examined the effects of high concentrations of serum (10% fetal bovine serum, FBS), as well as the cytokine interferon-gamma (IFN-gamma), on an oligodendrocyte cell line, MOCH-1 cells. These cells changed from phase-bright, small round cells with multiple thin, branched processes in 1% FBS medium to flat, fibroblast-like cells with large cell bodies when cultured in 10% FBS medium or 1% FBS medium containing IFN-gamma. These morphological changes were accompanied by a large increase in expression of the astrocyte marker, glial fibrillary acidic protein (GFAP), as detected by Northern and Western blot analyses. In addition, Northern blot and fluorescence-activated cell sorting analyses revealed that IFN-gamma induced a very large increase in major histocompatibility complex (MHC) class I expression in MOCH-1 cells. MHC class II mRNA induction by IFN-gamma was also seen. In contrast, 10% FBS did not elevate either MHC class I or class II mRNA levels in MOCH-1 cells. The morphological and molecular effects of 10% FBS and IFN-gamma were reversible. We suggest that the response of MOCH-1 cells to high concentrations of serum and IFN-gamma may reflect an important in vivo response to oligodendrocytes to perturbations that occur in demyelinating disorders.

Animals↗
PubMed1990

Magnetic resonance imaging of experimental demyelinating lesions.

An animal model of central nervous system demyelination was created by injecting rat internal capsules with lysophosphatidylcholine (LPC). The resulting chemically induced demyelinating lesions were readily visible in T1-weighted spin-echo, T2 weighted spin-echo, and inversion-recovery magnetic resonance imaging (MRI) sequences. Changes in lesions were followed over 8 weeks and correlated with histopathology. Histologically, lesions were characterized initially by an acute, inflammatory phase with edema and blood-brain barrier breakdown, followed by macrophage-mediated removal of myelin debris and finally by remyelination after 3 to 4 weeks. MRI can differentiate lesion stages in the LPC model and may be useful in investigating mechanistic aspects of the demyelinating process. In addition the well-localized lesions may be amenable to study by techniques of volume-localized NMR spectroscopy.

Animals↗
PubMed2002

Severe sensory ataxia and demyelinating polyneuropathy with IgM anti-GM2 and GalNAc-GD1A antibodies.

Several polyneuropathy syndromes have been described with polyclonal serum immunoglobulin G (IgG) or immunoglobulin M (IgM) binding to gangliosides GM2 and GalNAc-GD1a that contain the terminal trisaccharide moiety GalNAc(beta1-4)Gal(alpha2-3)NeuAc. We describe the clinical and electrodiagnostic features in two patients with serum IgM monoclonal anti-GM2 and anti-GalNAc-GD1a antibodies. These patients had slowly progressive, panmodal sensory loss with severe sensory ataxia. Electrodiagnostic testing showed demyelinating features. Prominent improvement in gait ataxia occurred after treatment with human immune globulin but not after other immunomodulating therapies. Enzyme-linked immunoabsorbent assay and thin-layer chromatography demonstrate that the patient's serum monoclonal IgM bound to gangliosides GM2 and GalNac-GD1a but not to gangliosides without the GalNAc(beta1-4)Gal(alpha2-3)NeuAc moiety. This neuropathy differs from previously reported neuropathy syndromes associated with polyclonal GM2 and GalNAc-GD1a antibodies and from other chronic demyelinating polyneuropathies. We conclude that a distinct syndrome of chronic demyelinating neuropathy with sensory ataxia, unresponsive to corticosteroids, is associated with monoclonal IgM binding to gangliosides with a terminal GalNAc(beta1-4)Gal(alpha2-3)NeuAc trisaccharide moiety. Diagnosis of this syndrome is important to direct appropriate treatment.

Ataxia↗
PubMed2003

Diagnostic value of nerve biopsy for atypical chronic inflammatory demyelinating polyneuropathy: evaluation of eight cases.

The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) relies primarily on clinical and electrophysiologic examination, but the nerve biopsy findings may be supportive, especially in atypical cases. In order to define the usefulness of nerve biopsy in this disease, we retrospectively studied 44 consecutive patients whom we classified as having CIDP on pathological grounds. We found that 8 of these 44 patients had pathological findings indicative of CIDP but did not meet any of the usually accepted electrophysiological criteria for its diagnosis. Among these eight patients, five responded favorably to conventional therapy. All of these eight patients had an electrophysiological pattern of generalized axonopathy with additional subtle findings suggestive of demyelination that prompted us to perform a nerve biopsy. Our data suggest that a significant number of patients with unrecognized CIDP are erroneously classified as having chronic idiopathic axonal polyneuropathy. CIDP should be suspected if the electrophysiological examination displays subtle abnormalities suggestive of demyelination, even in the presence of a prominent axonal pattern. Nerve biopsy in these patients may reveal abnormalities suggestive of CIDP and guide therapeutic options.

Action Potentials↗