Features Of Experimental Autoimmune Encephalomyelitis Research Articles

Neuroprotective Effects of Sinomenine on Experimental Autoimmune Encephalomyelitis via Anti-Inflammatory and Nrf2-Dependent Anti-Oxidative Stress Activity.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Sinomenine (SIN), a bioactive alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, has powerful anti-inflammatory and immunosuppressive therapeutic benefits. In our previous research, we found that SIN increased resistance to oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in PC12 neuronal cells. However, whether SIN can improve the symptoms and pathological features of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, via the Nrf2 signaling pathway remains unclear. EAE was immunized followed by SIN treatment. Then we evaluated the effects of SIN in EAE. Subsequently, primary microglia were cultured to explore the effect of SIN on microglia activation. Further, the levels of Nrf2 and its downstream molecules were detected to assess the molecular mechanisms of SIN. We demonstrated that SIN effectively ameliorated the severity of EAE, accompanied by a reduction in the demyelination, axonal damage and inhibition of inflammatory cell infiltration. Mechanistically, SIN decreased the inflammatory cytokines expression, and suppressed microglia and astrocytes activation in EAE mice. Furthermore, SIN suppressed lipopolysaccharide (LPS)-induced microglial activation and the production of pro-inflammatory factors in vitro. Moreover, SIN inhibited oxidative stress via the activation of the Nrf2 signaling pathway. Our work proves that SIN exerts its neuroprotective effects by the Nrf2-dependent anti-oxidative stress and diminishing neuroinflammation, suggesting that the "antioxiflammation" effect of SIN is expected to be an ideal treatment strategy for MS/EAE.

Induction and Diverse Assessment Indicators of Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a typical autoimmune disease of the central nervous system (CNS) characterized by inflammatory infiltration, demyelination, and axonal damage. Currently, there are no measures to cure MS completely, but multiple disease-modifying therapies (DMT) are available to control and mitigate disease progression. There are significant similarities between the CNS pathological features of experimental autoimmune encephalomyelitis (EAE) and MS patients. EAE has been widely used as a representative model to determine MS drugs' efficacy and explore the development of new therapies for MS disease. Active induction of EAE in mice has a stable and reproducible effect and is particularly suitable for studying the effects of drugs or genes on autoimmune neuroinflammation. The method of immunizing C57BL/6J mice with myelin oligodendrocyte glycoprotein (MOG35-55) and the daily assessment of disease symptoms using a clinical scoring system is mainly shared. Given the complex etiology of MS with diverse clinical manifestations, the existing clinical scoring system can't satisfy the assessment of disease treatment. To avoid the shortcomings of a single intervention, new indicators to assess EAE based on clinical manifestations of anxiety-like moods and osteoporosis in MS patients are created to provide a more comprehensive assessment of MS treatment.

Employing metabolomic approaches to determine the influence of age on experimental autoimmune encephalomyelitis (EAE)

The immune system plays a critical role not only in homeostasis of the body but also in pathogenesis. Autoimmunity and dysregulation of the immune balance are closely related to age. To examine the influence of age on autoimmunity, the pathophysiological features of experimental autoimmune encephalomyelitis (EAE) induced at different ages were elucidated on the basis of plasma-level metabolic changes. In the present study, female 6 week-old (6 W) and 15 month-old (15 M) C57BL/6 mice were immunized for EAE induction. The plasma and tissue samples were collected to determine the phenotypic characteristics. The activity of NADPH oxidase in plasma and the IL-6 concentrations in the brain and spinal cord were higher in both EAE groups compared to those in the control groups as well as in the 15 M EAE (15 M-E) group compared to those in the 6 W EAE (6 W-E) group. The metabolomic profiles related to characteristics of EAE were characterized by the biosynthesis of unsaturated fatty acids and the metabolism of tryptophan, tyrosine and sphingolipid. The reduced availability of unsaturated fatty acids and perturbations in tryptophan metabolism were high risk factors for EAE development regardless of age. The changes in tyrosine metabolism and sphingolipid metabolites were more dramatic in the 15 M-E group. From these findings, it can be concluded that changes in unsaturated fatty acid and tryptophan metabolism contributed to the development of EAE, whereas changes in sphingolipid and tyrosine metabolism, which corresponded to age, were additional risk factors that influenced the incidence and severity of EAE.

Oleacein Attenuates the Pathogenesis of Experimental Autoimmune Encephalomyelitis through Both Antioxidant and Anti-Inflammatory Effects.

Oxidative stress and proinflammatory cytokines are factors affecting multiple sclerosis (MS) disease progression. Oleacein (OLE), an olive secoiridoid, possesses powerful antioxidant and anti-inflammatory activities, which suggests its potential application to treat neuroinflammatory disorders. Herein, we investigated the impact of OLE on the main clinic-pathological features of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, including paralysis, demyelination, central nervous system (CNS) inflammation/oxidative stress and blood-brain barrier (BBB) breakdown. Methods: Mice were immunized with the myelin oligodendrocyte glycoprotein peptide, MOG35-55, to induce EAE, and OLE was administrated from immunization day. Serum, optic nerve, spinal cord and cerebellum were collected to evaluate immunomodulatory activities at a systemic level, as well as within the CNS. Additionally, BV2 microglia and the retinal ganglion cell line RGC-5 were used to confirm the direct effect of OLE on CNS-resident cells. Results: We show that OLE treatment effectively reduced clinical score and histological signs typical of EAE. Histological evaluation confirmed a decrease in leukocyte infiltration, demyelination, BBB disruption and superoxide anion accumulation in CNS tissues of OLE-treated EAE mice compared to untreated ones. OLE significantly decreased expression of proinflammatory cytokines (IL-13, TNFα, GM-CSF, MCP-1 and IL-1β), while it increased the anti-inflammatory cytokine IL-10. Serum levels of anti-MOG35-55 antibodies were also lower in OLE-treated EAE mice. Further, OLE significantly diminished the presence of oxidative system parameters, while upregulated the ROS disruptor, Sestrin-3. Mechanistically, OLE prevented NLRP3 expression, phosphorylation of p65-NF-κB and reduced the synthesis of proinflammatory mediators induced by relevant inflammatory stimuli in BV2 cells. OLE did not affect viability or the phagocytic capabilities of BV2 microglia. In addition, apoptosis of RGC-5 induced by oxidative stressors was also prevented by OLE. Conclusion: Altogether, our results show that the antioxidant and anti-inflammatory OLE has neuroprotective effects in the CNS of EAE mice, pointing out this natural product as a candidate to consider for research on MS treatments.

Acamprosate Protects Against Adjuvant-Induced Arthritis in Rats via Blocking the ERK/MAPK and NF-κB Signaling Pathway.

Osteoarthritis is a type of joint disease that results from the breakdown of joint cartilage and underlying bone and is believed to be caused by mechanical stress on the joint and low-grade inflammatory processes. Acamprosate significantly ameliorates the pathological features of experimental autoimmune encephalomyelitis due to its anti-inflammatory effect. The aims of the present study were to investigate the anti-arthritis activities of acamprosate and elucidate the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced by intradermal injection of complete Freund's adjuvant. Male Wistar rats were randomly divided into five groups: (1) sham control group, (2) AIA group, (3) acamprosate 10mg/kg (AIA + ACA10), (4) acamprosate 30mg/kg (AIA + ACA30), and (5) acamprosate 100mg/kg (AIA + ACA100). Paw swelling and the arthritis index were measured, and the production of IL-1β, IL-6, and TNF-α was detected by ELISA in serum. The expression of inflammation-related molecules, including c-Raf, ERK1/2, and NF-κB, was determined by Western blotting. We found that acamprosate significantly suppressed paw swelling and the arthritis index in AIA rats. Moreover, acamprosate also significantly suppressed the production of TNF-α, IL-1β, and IL-6 in serum, which is elevated by AIA induction. Finally, acamprosate inhibited p-c-Raf and p-ERK1/2 and NF-κB activation after AIA treatment. These results indicate that acamprosate has an anti-inflammatory effect on adjuvant-induced arthritic rats via inhibiting the ERK/MAPK and NF-κB signaling pathways, and acamprosate may serve as a promising novel therapeutic agent for osteoarthritis.

S-allyl cysteine improves clinical and neuropathological features of experimental autoimmune encephalomyelitis in C57BL/6 mice

Multiple sclerosis (MS) is a deleterious autoimmune and demyelinating disorder of the central nervous system with debilitating sensory and motor complications. There is still no definite cure for it and the main focus for its treatment mostly pivots around subsiding its severity and recurrence. Experimental autoimmune encephalomyelitis (EAE) is an established animal model of MS. S-allyl cysteine (SAC) is the active and main constituent of aged garlic extract with anti-inflammatory and neuroprotective property. This study was conducted to evaluate its possible protective effect in EAE model of MS. SAC was administered p.o. at a dose of 50 mg/kg/day to female C57BL/6 mice immunized with myelin oligodendrocytic glycoprotein (MOG35-55). Results showed that SAC is capable to alleviate clinical signs and severity of the disease and improved lumbar spinal cord tissue level of tumor necrosis factor α (TNFa), interleukin 17 (IL-17), activity-dependent neuroprotector homeobox (ADNP), microtubule-associated proteins 1A/1 B light chain 3A (MAP1LC3A), and matrix metalloproteinase 9 (MMP-9). In addition, SAC attenuated inflammatory cell infiltration, axonal demyelination, and axonal loss in lumbar spinal cord in EAE group, as demonstrated by H & E, Luxol fast blue (LFB), and Bielschowsky silver staining, respectively. Taken together, SAC could mitigate severity of MOG35-55-induced EAE as a valid model of MS via amelioration of pathogenic molecular mechanisms responsible for neuroinflammation and axonal damage.

Cyclic MOG35–55 ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis

EAE is induced to susceptible mice using linear peptides of myelin proteins of the central nervous system. Specific peptide motifs within the peptide-binding groove of the MHC peptide-complex determines the affinity of the peptide in each animal and the consequent T-cell receptor recognition and activation of the cell. Altered peptide ligand (APL) vaccination is a novel approach based on an effort to induce T-cell tolerance or alter cytokine profile from pro-inflammatory to anti-inflammatory. In the present study we synthesized the MOG35–55 peptide and altered its 3-dimensional conformation to make it a cyclic one (c-MOG35–55). EAE was induced in C57BL/6 mice and pathology was studied on acute and chronic phase of the disease. Our data indicates that c-MOG35–55 peptide alone induces a mild transient acute phase without chronic axonopathy. Administration of the c-MOG35–55 peptide at a 1:1 ratio during disease induction significantly ameliorates clinical disease and underlying pathology, such as demyelination and axonopathy in the acute and chronic phases. Binding and structural studies revealed milder interactions between the c-MOG35–55 and mouse or human MHC class II alleles (H2-IAb and HLA-DR2). Collectively, we provide data supporting for the first time the concept that the cyclic modification of an established encephalitogenic peptide ameliorates the clinical outcomes and underlying pathological processes of EAE. Such a cyclic modification of linear peptides could provide a novel treatment approach for future, patient-selective, immunomodulative treatments of multiple sclerosis.

T-cell activation RhoGTPase-activating protein plays an important role in TH17-cell differentiation.

T-cell activation RhoGTPase-activating protein (TAGAP) is a GTPase-activating protein specific for RhoA that is exclusively expressed in activated T cells. Genome-wide association studies and metagenome SNPs analyses have indicated that TAGAP is associated with the pathogenesis of multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, celiac disease and multiple sclerosis. However, the precise function of TAGAP remains unclear. Because TH17 cells contribute to TAGAP-associated autoimmune diseases, we hypothesized that TAGAP plays key roles in the differentiation and/or function of TH17 cells. To evaluate this hypothesis, we analyzed the effect of TAGAP on TH17 differentiation in vitro and established a line of TAGAP-deficient mice. We found that TAGAP was required for TH17 differentiation in vitro and that the loss of TAGAP in mice ameliorated the clinical features of experimental autoimmune encephalomyelitis, indicating that TAGAP is critical for disease progression. We also demonstrated that TAGAP interacts with RhoH, an adapter protein that interacts with lck and ZAP70 in proximal TCR signaling. TAGAP competes with ZAP70 for RhoH binding, thereby inhibiting TCR-associated signal transduction. Consistent with these findings, TCR-induced ERK activation was increased in TAGAP-deficient T cells. Because the upregulation of TCR signaling inhibits Th17 differentiation, TAGAP may prevent TCR signaling activity from reaching the limit of the induction of TH17 cells. Collectively, our findings indicate that TAGAP is a novel factor required for TH17-cell differentiation and that TAGAP potentially represents a novel target of autoimmune disease therapies.

Prevention and Mitigation of Experimental Autoimmune Encephalomyelitis by Murine β-Defensins via Induction of Regulatory T Cells

The antimicrobial peptide murine β-defensin-14 (mBD14) was found to exert, in addition to its antimicrobial activity, the capacity to induce regulatory T cells as demonstrated in the model of contact hypersensitivity. Because it is induced by ultraviolet radiation, mBD14 may contribute to the antigen-specific immunosuppression by ultraviolet radiation. To prove whether this applies also for other immunologic models and because ultraviolet radiation appears to have beneficial effects on multiple sclerosis, we utilized the model of experimental autoimmune encephalomyelitis. Injection of mBD14 into mice before immunization with myelin oligodendrocyte glycoprotein caused amelioration of the disease with less central nervous system inflammation and decreased levels of proinflammatory cytokines and cytotoxic T cells. The beneficial effect was due to Foxp3(+) regulatory T cells because it was lost on in vivo depletion of regulatory T cells. mBD14, however, also acts in a therapeutic setting, because injection of mBD14 into mice with clinical features of experimental autoimmune encephalomyelitis reduced the clinical score significantly. Human β-defensin-3, the human orthologue of mBD14, induced in vitro regulatory T cell-specific markers in CD4(+)CD25(-) T cells, shifting these nonregulatory cells into a regulatory phenotype with suppressive features. Thus, defensins may represent candidates worth being further pursued for the therapy of multiple sclerosis.

The therapeutic effects of MSc1 nanocomplex, synthesized by nanochelating technology, on experimental autoimmune encephalomyelitic C57/BL6 mice.

PurposeCurrently approved therapies for multiple sclerosis (MS) at best only slow down its progression. Therefore, it is necessary to utilize novel technologies in order to synthesize smart multifunctional structures. In the present study, for the first time we evaluated the therapeutic potential of MSc1 nanocomplex, which was designed based on novel nanochelating technology.Materials and methodsMSc1 cell-protection capacity, with and without iron bond, was evaluated against hydrogen peroxide (H2O2)-induced oxidative stress in cultured rat pheochromocytoma-12 cells. The ability of MSc1 to maintain iron bond at pH ranges of 1–7 was evaluated. Nanocomplex toxicity was examined by estimating the intraperitoneal median lethal dose (LD50). Experimental autoimmune encephalomyelitic mice were injected with MSc1 14 days after disease induction, when the clinical symptoms appeared. The clinical score, body weight, and disease-induced mortality were monitored until day 54. In the end, after collecting blood samples for assessing hemoglobin and red blood cell count, the brains and livers of the mice were isolated for hematoxylin and eosin staining and analysis of iron content, respectively.ResultsThe results showed that MSc1 prevented H2O2-induced cell death even after binding with iron, and it preserved its bond with iron constant at pH ranges 1–7. The nanocomplex intraperitoneal LD50 was 1,776.59 mg/kg. MSc1 prompted therapeutic behavior and improved the disabling features of experimental autoimmune encephalomyelitis, which was confirmed by decreased clinical scores versus increased body mass and 100% survival probability. It did not cause any adverse effects on hemoglobin or red blood cell count. Histopathological studies showed no neural loss or lymphocyte infiltration in MSc1-treated mice, while the hepatic iron content was also normal.ConclusionThese results demonstrate that MSc1 could be a promising beneficial novel agent and has the capacity to be evaluated in further studies.

IPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF

The possibility of generating neural stem/precursor cells (NPCs) from induced pluripotent stem cells (iPSCs) has opened a new avenue of research that might nurture bench-to-bedside translation of cell transplantation protocols in central nervous system myelin disorders. Here we show that mouse iPSC-derived NPCs (miPSC-NPCs)-when intrathecally transplanted after disease onset-ameliorate clinical and pathological features of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Transplanted miPSC-NPCs exert the neuroprotective effect not through cell replacement, but through the secretion of leukaemia inhibitory factor that promotes survival, differentiation and the remyelination capacity of both endogenous oligodendrocyte precursors and mature oligodendrocytes. The early preservation of tissue integrity limits blood-brain barrier damage and central nervous system infiltration of blood-borne encephalitogenic leukocytes, ultimately responsible for demyelination and axonal damage. While proposing a novel mechanism of action, our results further expand the therapeutic potential of NPCs derived from iPSCs in myelin disorders.

Bee Venom Attenuates Experimental Autoimmune Encephalomyelitis through Direct Effets on CD4+CD25+FOXP3+ T Cells

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to substantial disability through deficits of sensation and of motor, autonomic, and neuro-cognitive function. Many clinical and pathological features of experimental autoimmune encephalomyelitis (EAE) show close similarity to MS. Bee venom (BV) has been used in the practice of oriental medicine and evidence from the literature indicates that BV plays an anti-inflammatory or anti-nociceptive role against inflammatory reactions associated with arthritis and other inflammatory diseases. The purpose of the present study was to determine whether BV could suppress immune cell differentiation and infiltration into spinal cord on EAE mice commonly used as a model for MS. BV treatment increased the population of CD4+CD25+Foxp3+ T cells and inhibited CD4+ T-cell proliferation in vitro. In vivo, BV treatment increased the population of CD4+CD25+Foxp3+ T cells. Furthermore, BV administration reduced the severity of EAE while concurrently decreasing INF-γ producing CD4+T cells, IL-17A producing CD4+T cells and inflammatory cytokine production including INF-γ, IL-17A, TNF and IL-6. BV-treated animals exhibited less infiltration and preserved morphology compared to saline-treated animals. Interestingly, the therapeutic effects of BV on EAE disappeared when CD4+CD25+Foxp3+ T cells were depleted by using anti-CD25 antibody. Our research suggests that BV could be a potential therapeutic agent for antiinflammatory effects in an animal model of EAE.

Acamprosate modulates experimental autoimmune encephalomyelitis

This pilot study aimed to determine the efficacy of acamprosate (N-acetyl homotaurine) in reducing the pathological features of experimental autoimmune encephalomyelitis (EAE) which is an animal model for multiple sclerosis (MS). The amino acid taurine has multiple biological activities including immunomodulation and neuromodulation. The synthetic acetylated taurine derivative, acamprosate, which crosses the blood-brain barrier more readily compared to taurine, is currently being used for the prevention of alcohol withdrawal symptoms associated with enhanced glutamatergic receptor function and GABA receptor hypofunction. EAE was induced in C57BL/6 female mice with myelin oligodendrocyte glyocoprotein, amino acid 35-55. Mice were treated with 20, 100 and 500 mg/kg acamprosate for 21 days. Neurological scores at disease peak were reduced by 21, 64 and 9% in the 20, 100 and 500 mg/kg groups, respectively. Neurological improvement in the 100 mg/kg group correlated with a reduction in numbers of inflammatory lesions and the extent of CNS demyelination. Blood TNF-α levels were significantly reduced in the 500 mg/kg group. Acamprosate and other taurine analogs have a potential for future MS therapy.

Immune Regulatory Neural Stem/Precursor Cells Protect from Central Nervous System Autoimmunity by Restraining Dendritic Cell Function

BackgroundThe systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs.Methodology/Principal FindingsTo achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific–BMP-4-dependent–mechanism hindering the DC maturation.Conclusion/SignificanceThe study described herein, identifies the first member of the TGF β/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.

Clinical, Pathological, and Immunologic Aspects of the Multiple Sclerosis Model in Common Marmosets (Callithrix jacchus)

The efficacy of many new immunomodulatory therapies for multiple sclerosis (MS) patients has often been disappointing, reflecting our incomplete understanding of this enigmatic disease. There is a growing awareness that, at least in part, there may be limited applicability to the human disease of results obtained in the widely studied MS model experimental autoimmune encephalomyelitis in rodents. This review describes the experimental autoimmune encephalomyelitis model developed in a small neotropical primate, the common marmoset (Callithrix jacchus). The model has features including clinicopathologic correlation patterns, lesion heterogeneity, immunologic mechanisms, and disease markers that more closely mimic the human disease. Several unique features of experimental autoimmune encephalomyelitis in marmosets, together with their outbred nature and close genetic and immunologic similarities to humans, create an attractive experimental model for translational research into MS, particularly for the preclinical evaluation of new biologic therapeutic molecules that cannot be investigated in rodents because of their species specificity. Moreover, this model provides new insights into possible pathogenetic mechanisms in MS.

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin antigens: IV. Suppression of chronic relapsing disease in the lewis rat and strain 13 guinea pig

Oral administration of proteins is a long-recognized method of inducing antigen-specific peripheral immune tolerance. We previously showed that oral administration of myelin basic protein suppresses monophasic experimental autoimmune encephalomyelitis in the Lewis rat when it is given in association with immunization and prior to disease onset. As a potential therapy for human autoimmune disease, it is crucial to determine whether oral tolerance can ameliorate an ongoing immune response. We therefore asked whether oral administration of myelin antigens, after sensitization and disease expression has occurred, could affect immunological, clinical, or pathological features of experimental autoimmune encephalomyelitis. Chronic relapsing experimental autoimmune encephalomyelitis was induced in the Lewis rat and strain 13 guinea pig by immunization with whole guinea pig cord homogenate, complete Freund's adjuvant, and Mycobacterium tuberculosis. Following recovery from the first attack, animals were orally given bovine myelin, guinea pig myelin, or guinea pig myelin basic protein three times per week for up to 3 months. Animals receiving myelin products orally had decreased severity and frequency of clinical relapses, decreased delayed-type hypersensitivity responses to myelin antigens, diminished inflammation in the central nervous system (CNS), and decreased areas of CNS demyelination. In the rat, guinea pig myelin basic protein was as effective as guinea pig myelin in ameliorating the disease and also resulted in decreased serum anti-myelin basic protein antibody levels. No exacerbation of disease or worsening of pathological findings occurred in the animals given myelin products. These results demonstrate that oral administration of myelin antigens can suppress chronic relapsing experimental autoimmune encephalomyelitis and have direct relevance to therapy of human demyelinating disorders such as multiple sclerosis.