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PubMed1996

Augmented expression of tumour necrosis factor-alpha and lymphotoxin in mononuclear cells in multiple sclerosis and optic neuritis.

The involvement of proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT) in multiple sclerosis is suggested by the parallel occurrence of these proinflammatory cytokines in acute and chronic active multiple sclerosis brain lesions. We describe the use of in situ hybridization with radiolabelled cDNA oligonucleotide probes to detect and enumerate TNF-alpha and LT mRNA expressing mononuclear cells without culture, and after culture in the presence of myelin basic protein (MBP), control antigens or without antigen. Compared with patients with aseptic meningo-encephalitis, non-inflammatory neurological diseases and healthy controls, the multiple sclerosis patients had elevated numbers of TNF-alpha and LT mRNA expressing mononuclear cells in blood when enumerated without previous culture, and also after culture with MBP. The MBP-induced upregulation of TNF-alpha and LT was major histocompatibility complex (MHC) class II molecule dependent. Tumour necrosis factor-alpha mRNA expressing mononuclear cells were further enriched in the multiple sclerosis patients' CSF. Positive correlations were observed in multiple sclerosis between TNF-alpha and LT mRNA expressing blood mononuclear cells, MBP-reactive TNF-alpha and LT mRNA expressing cells, and TNF-alpha and interferon-gamma (INF-gamma) mRNA expressing mononuclear cells. Upregulation of TNF-alpha correlated positively with exacerbation, enhanced disability and the secondary progressive phase of multiple sclerosis. Patients with optic neuritis, in many instances representing very early multiple sclerosis, had TNF-alpha and LT positive blood mononuclear cells that were elevated to the same extent as patients with clinically definite multiple sclerosis. The findings support the hypothesis that TNF-alpha and LT play a harmful role in the development of multiple sclerosis and suggest that TNF-alpha could be useful as a disease activity marker in multiple sclerosis.

Adult↗
PubMed1997

A combined inhibitor of matrix metalloproteinase activity and tumour necrosis factor-alpha processing attenuates experimental autoimmune neuritis.

Matrix metalloproteinases (MMPs) and the cytokine tumour necrosis factor (TNF)-alpha are implicated in the pathology of inflammatory demyelinating diseases of the CNS, and may also be involved in peripheral demyelinating diseases such as acute inflammatory demyelinating polyradiculoneuropathy. We have tested an inhibitor of MMP activity and TNF-alpha processing, BB-1101, in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome. Treatment with BB-1101 from the time of immunization prevented the development of EAN, and when given from the onset of symptoms, it significantly reduced disease severity. These results indicate that MMPs and/or TNF-alpha are involved in the pathogenesis of EAN, and that drugs of this type may have potential as novel therapeutic agents in the therapy of peripheral nervous system demyelinating diseases.

Animals↗
PubMed1997

Human immunoglobulin ameliorates rat experimental autoimmune neuritis.

Human immunoglobulin is an effective treatment for Guillain-Barré syndrome, although the mechanism of action is not understood. We have investigated the effect of human immunoglobulin in an animal model of Guillain-Barré syndrome, namely experimental autoimmune neuritis (EAN), induced in Lewis rats by immunization with bovine spinal root myelin. Human immunoglobulin administered intraperitoneally at the time of onset of disease accelerated the rate of recovery from EAN. This improvement was associated with a reduction in the titre of anti-rat myelin antibodies and may be due to earlier remyelination of demyelinated nerve fibres. This model may facilitate further investigation of the mechanism of therapeutic action of immunoglobulin in inflammatory neuropathy.

Animals↗
PubMed1998

Induction of experimental autoimmune neuritis with peripheral myelin protein-22.

Two myelin proteins, P2 basic protein and P0 glycoprotein, can induce experimental autoimmune neuritis (EAN), a model of human inflammatory neuropathy. We investigated whether peripheral nerve myelin protein-22 (PMP22), the gene for which is duplicated in hereditary motor sensory neuropathy type la, can also induce EAN. PMP22 cDNA produced by the reverse transcriptase-polymerase chain reaction from rat sciatic nerve was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase (GST). Ten Lewis rats were immunized with purified PMP22 fusion protein (50-100 microg) and eight controls with the same amount of GST. Two additional animals were immunized with each of two peptides (250 microg) of the human PMP22 extracellular sequences. Animals were examined daily until 20 days following immunization, when they underwent neurophysiological examination. A serum sample was then taken, prior to perfusion with glutaraldehyde and removal of the sciatic nerves and cauda equina. PMP22-immunized animals developed antibodies to the fusion protein and five out of 10 developed limp tails. No changes were observed in controls immunized with GST or in animals immunized with peptide. The mean compound motor action potentials elicited in the foot muscles by stimulation of the sciatic nerve at the sciatic notch and of the tibial nerve at the ankle were significantly reduced in the PMP22-immunized group (P < 0.05). Spinal roots from the group of animals immunized with PMP22 showed sparse infiltration of mononuclear cells, oedema and demyelination. PMP22 now deserves consideration as an autoantigen in human acute inflammatory demyelinating polyradiculoneuropathy.

Action Potentials↗
PubMed1998

Matrix metalloproteinase expression during experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.

Animals↗
PubMed1998

Perceptual and oculomotor effects of neck muscle vibration in vestibular neuritis. Ipsilateral somatosensory substitution of vestibular function.

Afferent cervical somatosensory input may substitute for absent vestibular information as part of central vestibular compensation after unilateral peripheral vestibular deficit. In order to determine the particular contribution of neck muscle spindles to the perception of body orientation and to the oculomotor system, we measured (i) the subjective visual straight ahead (SVA) by psychophysical tests and (ii) the changes in eye position by video-nystagmography during unilateral stimulation of the posterior neck muscles by vibration (100 Hz). Twenty-five patients with subacute unilateral vestibular lesion (vestibular neuritis) and 25 controls participated in the study. Vibration elicited a horizontal displacement of SVA towards the side of stimulation in all subjects. Mean displacement (+/- SD) was 3.28 +/- 2.96 degrees for right-side and 3.45 +/- 2.93 degrees for left-side stimulation in controls. Muscle stimulation on the patients' lesion side induced a significantly higher displacement (11.51 +/- 6.63 degrees) than contralateral stimulation (3.04 +/- 2.95 degrees, P < 0.01, paired Student's t test). The mean difference during stimulation between the two sides in the patients was 8.02 +/- 5.52 degrees; in the controls, however, it was only 0.74 +/- 0.47 degree (P < 0.001, Student's t test). This asymmetry increased gradually in patients over a period of weeks, reaching a maximum at days 60-80 and declining thereafter. Videonystagmography revealed that ipsilateral stimulation in patients induced large horizontal eye deviations of up to 25 degrees towards the side of the lesion (9.1 +/- 7.6 degrees, n = 18). Contralateral stimulation induced only small shifts, which were within the range of controls. The correlation coefficient between displacement of the SVA and change in eye position was high (r = 0.94, P < 0.0001), indicating that the shift of SVA is the perceptual correlate of the directional change of gaze in space. This interpretation was supported by two control experiments in which the subject was required to (i) indicate the subjective straight ahead by finger-pointing with the eyes closed and (ii) adjust SVA when looking through horizontally reversing prisms. Vibration of neck muscles caused almost no displacement of the SVA when it was indicated by pointing with the eyes closed, but reversed the direction of the displacement if the subject wore reversing prisms. In summary, our data showed: (i) an increase in muscle spindle input following unilateral vestibular lesion; (ii) this increase is asymmetrical, restricted to the affected side, and gradually builds up over weeks; and (iii) the perceived effects during vibration are secondary to changes in eye position rather than changes in cortical representation of body orientation. This is the first study to demonstrate a unilateral increase in somatosensory weight, which substitutes for missing vestibular input.

Adolescent↗
PubMed1998

The role of the very late antigen-4 and its counterligand vascular cell adhesion molecule-1 in the pathogenesis of experimental autoimmune neuritis of the Lewis rat.

We have investigated the functional role of very late antigen-4 [VLA-4 (alpha4/beta1) integrin] and vascular cell adhesion molecule-1 (VCAM-1) in experimental autoimmune neuritis (EAN), an animal model of the Guillain-Barré syndrome, using neutralizing monoclonal antibodies (mAbs) as probes. Disease was induced by intravenous adoptive transfer of P2 specific T cells (AT-EAN), or by immunization with bovine myelin (active EAN). Preventive treatment with 500 microg anti-VLA-4 mAb (TA-2) or with an isotype control antibody was given in AT-EAN 4 h before cell transfer and at day 3. Intravenous injection of 500 microg anti-VCAM-1 mAb (5F10) or a corresponding isotype control was given in AT-EAN 4 h before disease induction, and at days 2, 4 and 6. Preventive treatment of active EAN with mAb to VLA-4 or VCAM-1 was performed at days 5, 9 and 13. On immunohistochemical examination, VCAM-1 in sciatic nerve was found to be upregulated at early stages of EAN (days 3-5 after T-cell transfer), whilst no expression was noted in healthy controls. In both EAN models, blockade of VLA-4 markedly attenuated disease severity. Blockade of VCAM-1 also significantly ameliorated the disease course and diminished T-cell infiltration in sciatic nerve, but to a lesser degree. These experiments demonstrate the critical role of VLA-4 in the pathogenesis of EAN and show that upregulation of VCAM-1 expression contributes, at least in part, to the progression of the disease in the early stages. Future studies are needed to assess the potential contribution of other VLA-4 ligands.

Animals↗
PubMed1999

Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat.

In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V)-region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies.

Adoptive Transfer↗
PubMed2001

Long-term remyelination after optic neuritis: A 2-year visual evoked potential and psychophysical serial study.

Thirty-one patients were followed-up, at 3-month intervals for the first year and at 6-month intervals for the second year, after an episode of optic neuritis. The object was to confirm previous evidence for a progressive shortening of visual evoked potential (VEP) latencies and to determine whether this is associated with any change in the clinical ocular examination, visual fields or contrast sensitivity. VEP latencies were found to decrease significantly during both the first and (less strikingly) the second year, the most marked changes occurring between 3 and 6 months. Contrast sensitivity improved during the first 9 months, but subsequently tended (non-significantly) to deteriorate. A similarly transient improvement in central visual field sensitivity was seen in a subgroup of patients with clinically overt multiple sclerosis. In the data from the acutely unaffected fellow eyes, no significant changes in VEP parameters or functional indices were observed. The findings extend those of a previous study which showed significant shortening of VEP latencies between 6 months and 3 years without significant functional improvement. Over this period, a significant prolongation of VEP latencies occurred in the asymptomatic fellow eye, accompanied by contrast sensitivity deterioration. Taken in conjunction, the two studies suggest that recovery processes involving remyelination or, possibly, ion channel reorganization proceed for at least 2 years. The concurrent effects of insidious demyelination and/or axonal degeneration (also occurring in the fellow optic nerve) are initially masked by the recovery process, but gradually become more evident. The functional benefits of the long-term recovery process are relatively minor and are usually reversed within a few years. Nevertheless, it is suggested that long-term remyelination may perform an important role in protecting demyelinated axons from degeneration. Understanding the factors which promote long-term remyelination may have significant implications for therapy in multiple sclerosis.

Adult↗
PubMed2001

Suppression of experimental autoimmune neuritis by leflunomide.

Leflunomide is a new immunosuppressive drug whose active metabolite, A77 1726, impairs cellular nucleotide metabolism by inhibiting the dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of de novo pyrimidine synthesis. Furthermore, A77 1726 suppresses tyrosine kinases involved in signal transduction pathways. We investigated the immunosuppressive effects of leflunomide in experimental autoimmune neuritis (EAN) in rats, which is a model of immune-mediated neuropathies. In EAN that was actively induced by subcutaneous injection of peripheral nerve myelin, leflunomide completely prevented paraparesis if applied orally from the day of immunization. Leflunomide was much more effective than azathioprine, which did not mitigate EAN at all. Even when leflunomide was administered therapeutically after the appearance of the first neuropathical signs, it halted the progression and markedly reduced the severity and duration of EAN. Inflammatory infiltrates, demyelination and axonal degeneration in sciatic nerve sections of leflunomide-treated EAN rats were strongly reduced. Leflunomide-treated rats did not mount autoantibodies as specified by ELISA (enzyme-linked immunosorbent assay) with a mixture of peripheral myelin proteins, including P2 and myelin basic protein. In EAN that was adoptively transferred by injection of neuritogenic cells of a P2-specific T-helper line, application of leflunomide also clearly reduced signs of disease. Additional injection of uridine did not neutralize the effect of leflunomide. Similarly, transfer of neuritogenic P2-specific T cells, which were activated in the presence of A77 1726 plus uridine in vitro, still resulted in reduced severity of adoptive transfer EAN in vivo, although proliferation of these cells in vitro was identical to that of control cells. The T-cell receptor-mediated in vitro activatability of a P2-specific T-cell hybridoma was diminished by high concentrations of A77 1726, as evidenced by reduced Ca(2+) flux into the cytosol. Together with the findings in adoptive transfer EAN, this indicates that the antiproliferative effect is probably not the only mechanism of immunosuppressive action by leflunomide. In summary, leflunomide suppresses EAN efficiently and may constitute a promising therapy for immune-mediated neuropathies.

Adoptive Transfer↗
PubMed1975

Carotid artery thrombosis, encephalitis, myelitis and optic neuritis associated with rubella virus infections.

The clinical, virological and pathological findings in 5 patients with neurological complications associated with rubella virus infection are described. The neurological illnesses began four to ten days after the rubella illnesses. The patients were all males aged between 6 and 17 years and were diagnosed during one non-epidemic year in a population of 1-5 million people. All the patients had rubella specific IgM in their sera. Two patients had no rash. In one of the patients who died, left internal carotid artery thrombosis and cerebral infarction were found at post-mortem. Rubella virus antigen and particles resembling rubella virus were found in the brain together with IgG and IgM in the same areas. This patient also had extensive liver necrosis. The other patient had a severe meningomyelitis and radiculitis and he recovered completely after two years. His serum rubella antibody rose significantly and was shown to leak into CSF during the acute stage of his illness. Three patients had a rash. Two of these patients had encephalitis: one recovered completely and the other had residual disability. The third patient had bilateral optic neuritis from which he recovered completely. Rubella specific IgM was, however, present in his serum for the abnormally long time of twenty-eight weeks indicating possible persistence of rubella virus.

Adolescent↗
PubMed2004

A serial MRI study following optic nerve mean area in acute optic neuritis.

This study assessed optic nerve mean area on serial MRI in a cohort of patients with a first episode of acute unilateral optic neuritis to assess the effects of a single acute inflammatory demyelinating lesion. Twenty-nine patients with a median delay from onset of visual symptoms of 13 days (range 7-24 days) were recruited. After a clinical examination and visual evoked potential (VEP) measurement, each patient had their optic nerves imaged with a coronal fat-saturated short echo fast fluid-attenuated inversion recovery sequence. Twenty-one patients had serial examinations after 2, 4, 8, 12, 26 and 52 weeks. In addition, 32 control subjects had their optic nerves imaged up to three times. The mean cross-sectional area of the intra-orbital portion of each optic nerve was calculated by a blinded observer using a computer-assisted contouring technique. At baseline, the mean area of diseased optic nerves was 16.1 mm2 compared with 13.4 mm2 for healthy contralateral optic nerves (20.1% higher, P < 0.0001) and 13.6 mm2 for controls (18.4% higher, P = 0.0003). The diseased optic nerve mean area declined over time, from initial swelling to later atrophy. The mean decline at 52 weeks was -0.0018 mm2/day (95% confidence interval -0.0038 to -0.00051). At 52 weeks, the mean area of diseased optic nerves was 11.3 mm2 compared with 12.8 mm2 for healthy contralateral optic nerves (11.7% lower, P = 0.032) and 13.1 mm2 for controls (13.7% lower, P = 0.008). The 52 week diseased optic nerve mean area was not significantly affected by the baseline mean area. There was an association between baseline optic nerve mean area and logMAR visual acuity (rS = 0.46, P = 0.012) and visual field mean deviation (rS = -0.55, P = 0.002), but there was no evidence of an association between 1 year mean area and visual outcome. There was no evidence of association between baseline, rates of decline or 1 year diseased optic nerve mean areas and any of the baseline, 1 year or time-averaged VEP variables. The present study shows a consistent pattern of changes associated with individual inflammatory demyelinating lesions in the optic nerve. Acutely, there was swelling, consistent with the presence of acute inflammation, which was related to visual impairment. Over the longer term, there was loss of tissue. The lack of association between 1 year optic nerve mean area and visual outcome may reflect a mild loss of tissue, redundancy or remodelling of function.

Acute Disease↗
PubMed2004

Axonal protection in experimental autoimmune neuritis by the sodium channel blocking agent flecainide.

Inflammatory demyelinating neuropathies such as Guillain-Barre syndrome (GBS) and its animal model, experimental autoimmune neuritis (EAN), are typically acute monophasic diseases of the PNS that can leave affected individuals with permanent disability due primarily to axonal degeneration. The mechanisms underlying the degeneration are not understood, but we have previously shown in vitro and in vivo that axons can degenerate when exposed to the inflammatory mediator nitric oxide, and that axons can be protected by application of the sodium channel-blocking agent, flecainide. Here we examine whether flecainide administration can similarly reduce axonal degeneration in the periphery in animals with EAN. EAN was induced in Lewis rats (n = 116, in three independent trials), and rats received either flecainide (Flec) (30 mg/kg/day) or vehicle (Veh) from the onset of disease expression. Flecainide administration significantly reduced the mean (SD) scores for neurological deficit at both the peak of disease (Flec: 5.7 (2.7), Veh: 8.0 (3.6), P < 0.001) and at the termination of the trials 25-29 days post-inoculation (Flec: 2.2 (2.4), Veh: 4.2 (4.2), P < 0.001). Histological examination of the tibial nerve of EAN animals revealed that flecainide provided significant protection against axonal degeneration so that 80.0% of the normal number of axons survived in flecainide-treated rats compared with 62.8% in vehicle-treated rats (P < 0.01). These findings may indicate a novel avenue for axonal protection in GBS and other inflammatory demyelinating neuropathies.

Animals↗
PubMed2000

Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis.

TNF-alpha has been implicated as a potentially detrimental cytokine in autoimmune disorders of the nervous system and has been reported to be elevated in antigen-specific therapy of experimental autoimmune neuritis (EAN) in vivo. To investigate the role of TNF-alpha in EAN in rats that had been subjected to antigen-specific therapy with human P2 protein, animals were cotreated with an anti-TNF-alpha neutralizing antibody and the effects of the antibody on disease determined. Using this strategy in adoptive transfer (AT-) EAN, antigen-induced T-cell apoptosis in inflamed sciatic nerve and in liver was reduced to levels observed in control animals indicating that TNF-alpha mediates antigen-induced apoptosis of inflammatory T-cells. Focal liver necrosis, which had been observed in earlier studies after antigen therapy in AT-EAN, was prevented by passive immunization with neutralizing anti-TNF-alpha antibody. Unexpectedly, neutralization of TNF-alpha only partly abolished the protective effect of antigen therapy on the overall disease course. This may indicate that inhibition of TNF-alpha exerts beneficial effects other than through T-cell apoptosis, or that some of the benefit of antigen therapy is mediated by other pathways. These results indicate that secretion of TNF-alpha during antigen therapy has the dual potential to mediate beneficial apoptosis of inflammatory T-cells in the inflammatory lesion and to induce liver damage as a severe side effect.

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

Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis by counter-regulation of autoreactive Th1 responses to peripheral myelin antigen.

Experimental autoimmune neuritis (EAN) is a demyelinating disease of the peripheral nervous system (PNS). This acute inflammatory disease is mediated by CD4+ T cells and bears significant similarities to the Guillain-Barré syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide 180-199 and Freund's complete adjuvant. Our data indicate that in 2 different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs of EAN. The suppression is associated with reduced inflammatory cell infiltration into the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a reduced mononuclear cell proliferation and IFN-gamma-secretion in the spleen. Increased numbers of IL-4 expressing cells and decreased numbers of IFN-gamma and TNF-alpha expressing cells were found in the PNS. Our results suggest that shifting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAb. In addition, anti-IL-18 mAb treatment reduced anti-P0 peptide 180-199 autoantibody responses, which may also contribute to EAN suppression. We conclude that endogenous IL-18 plays a critical role in the pathogenesis of autoimmune demyelinating disease of the PNS and that IL-18 antagonists may provide a new therapy for these diseases.

Animals↗
PubMed2004

Increased susceptibility to experimental autoimmune neuritis after upregulation of the autoreactive T cell response to peripheral myelin antigen in apolipoprotein E-deficient mice.

Experimental autoimmune neuritis (EAN), an acute demyelinating inflammatory disease of the peripheral nervous system (PNS), is a good model for the human counterpart, Guillain-Barré syndrome. Apolipoprotein E (ApoE), a 34 kDa glycosylated protein with multiple biological properties, has been linked both with the innate immune response of mice and with neurological disease. The present study investigated the previously unexplored role of ApoE in autoimmune-mediated demyelination. ApoE-deficient (apoE -/-) mice exhibited a greater susceptibility to EAN induced by the PNS myelin P0 protein peptide 180-199, as compared to wild type (apoE +/+) mice. The augmented susceptibility seen in apoE -/- mice was associated with increased inflammatory cell infiltrates in the PNS during the effector phase. Although the 2 groups of mice exhibited no quantitative or proportional differences in splenic lymphocyte populations, the apoE -/- mice showed enhanced antigen-specific proliferation of T cells of spleen, which is related to modified macrophage function, upregulation of Th1 and downregulation of Th2-autoreactive responses to P0 peptide. These effects were shown as increased numbers of IFN-gamma expressing cells in the spleen and of IFN-gamma, IL-12 and TNF-alpha expressing cells in the PNS, as well as a decreased IL-10 production by splenic cells in apoE -/- mice. In addition, apoE -/- mice had enhanced antigen-specific antibody responses, which might have contributed to their aggravated EAN. These data provide strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by upregulating IL-10, as well as by inhibiting Th1 responses and antigen-specific antibody formation. These data may aid the development of new and more effective therapeutic strategies for inflammatory and demyelinating diseases such as Guillain-Barré syndrome.

Analysis of Variance↗
PubMed1998

The effect of cyclooxygenase-2 inhibitor on experimental allergic neuritis.

We studied the effect of the cyclooxygenase (COX)-2 inhibitor nimesulide on experimental allergic neuritis (EAN). In rats fed with nimesulide starting on day 1 post inoculation, the clinical EAN score was significantly lower and the maximal clinical score was reduced compared with the control group. Even if given after the onset of clinical signs, the clinical score was reduced and improvement was faster than the control group. Nimesulide inhibited decreases in weight in the experimental group. The histopathological observations of the sciatic nerve showed a decreased incidence of degenerated nerve fibers in the experimental group. Although the exact mechanism of its efficacy is not clear, a COX-2 inhibitor may have potential as an additional therapeutic agent in human inflammatory neuropathies.

Amino Acid Sequence↗