MS Abstracts 9b-2g

  1. IL-18 Directs AutoReactive T-Cells and Promotes AutoDestruction in the Central Nervous System Via Induction of IFN-gamma by NK Cells
    J Immunol 2000 Sep 15;165(6):3099-3104

  2. Intracellular signalling and AntiViral effects of Interferons
    Dig Liver Dis 2000 Apr;32(3):257-63

  3. High-dose MethylPrednisolone reduces Cytokine-induced Adhesion Molecules on Human Brain Endothelium
    Can J Neurol Sci 2000 Aug;27(3):241-4

  4. Cardiac repolarization abnormalities in Multiple Sclerosis: Spinal Cord MRI correlates
    Muscle Nerve 2000 Aug;23(8):1284-6

  5. Tumor Necrosis Factor-alpha has few morphological effects within the Dorsal Columns of the Spinal Cord, in contrast to its effects in the Peripheral Nervous System
    J NeuroImmunol 2000 Jul 1;106(1-2):130-136

  6. Physiologic and functional responses of MS patients to body cooling
    Am J Phys Med Rehabil 2000 Sep-Oct;79(5):427-34

  7. Intramuscular Interferon-ß-1a Therapy Initiated during a First DeMyelinating Event in Multiple Sclerosis
    N Engl J Med 2000 Sep 28;343(13):898-904

  8. Genetics of Multiple Sclerosis
    Biomed Pharmacother 2000 Mar;54(2):103-6

  9. Multiple Sclerosis is associated with an imbalance between Tumor Necrosis Factor-alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-ß) treatment
    Clin Exp Immunol 2000 Apr;120(1):147-53

  10. Diagnostic usefullness of OligoClonal ImmunoGlobulin G bands in CerebroSpinal Fluid using isoelectric focusing in early diagnosis of Multiple Sclerosis
    Ann Biol Clin (Paris) 2000 Mar;58(2):187-193


IL-18 Directs AutoReactive T-Cells And Promotes AutoDestruction In The Central Nervous System Via Induction Of IFN-gamma By NK Cells

Shi FD, Takeda K, Akira S, Sarvetnick N, Ljunggren HG
J Immunol 2000 Sep 15;165(6):3099-3104
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden;Dept of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka University, Osaka, Japan
PMID# 10975822; UI# 20432290

IL-18 promotes NK Cell and Th1 Cell activity and may bridge Innate and Adaptive Immune Responses. Myelin Oligodendrocyte Glycoprotein (MOG) is a Myelin component of the CNS and is a candidate AutoAntigen in Multiple Sclerosis.

In the present study we show that IL-18-deficient (IL-18-/-) mice are defective in mounting AutoReactive Th1 and AutoAntiBody responses and are resistant to MOG35-55 Peptide-induced AutoImmune EncephaloMyelitis.

IL-18 administration enhances the disease severity in wild-type mice and restores the ability to generate Th1 response in the IL-18-/- mice.

This restoration was abrogated in NK Cell-depleted mice, indicating that the action of IL-18 in promoting the generation of MOG-specific Th Cells was dependent on NK Cells.

Furthermore, transfer of NK Cells from recombinase-activating Gene 1-/- mice, but not from recombinase-activating Gene 1/IFN-gamma-/- mice, rescued the defective Th1 responses in IL-18-/- mice and rendered IL-18-/- mice susceptible to the induction of AutoImmune EncephaloMyelitis.

Thus, IL-18 can direct AutoReactive T-Cells and promote AutoDestruction in the CNS at least in part via induction of IFN-gamma by NK Cells.


Intracellular Signalling And AntiViral Effects Of Interferons

Heim MH
Dig Liver Dis 2000 Apr;32(3):257-63
Univ Hospital Basel, Dept of Gastroenterology, Switzerland
PMID# 10975779; UI# 20424578

More than 4 decades after their discovery, Interferons are used now in daily clinical practice for the treatment of Chronic Viral Hepatitis, Multiple Sclerosis, Chronic Granulomatous Disease, and malignant disease such as Hairy Cell Leukaemia, Chronic Myeloid Leukaemia, Kaposi's Sarcoma, Multiple Myeloma and Malignant Melanoma.

In general, treatment with Interferons is successful in only a fraction of the patients suffering from these diseases. The reasons for treatment failures in many patients are not understood a present.

The discovery of the Jak-Stat pathway as the principal signalling pathway for Interferons opens new research options for a better understanding of Interferon resistance in various diseases.

Defective Jak-Stat signal transduction has now been described in cells expressing HBV proteins, in cells expressing HCV proteins, and in cell lines derived from malignant melanomas.

A better understanding of these signalling defects might lead to new therapeutic strategies making Interferons more effective in a larger percentage of patients.


High-Dose MethylPrednisolone Reduces Cytokine-Induced Adhesion Molecules On Human Brain Endothelium

Gelati M, Corsini E, Dufour A, Massa G, Giombini S, Solero CL, Salmaggi A
Can J Neurol Sci 2000 Aug;27(3):241-4
Istituto Nazionale Neurologico C. Besta, Milano, Italy
PMID# 10975537; UI# 20427277

We investigated the in vitro effects of low- and high-dose MethylPrednisolone (MP) on the Cytokine-induced expression of HLA-DR, ICAM-1 and VCAM-1 on Human Brain MicroVessel Endothelial Cells (HBMECs).

Brain Endothelium was obtained from MicroVessels included in the Apparently Normal White Matter of surgical specimens of nine patients.

Cells were stained with MonoClonal AntiBodies anti-HLA-DR, anti-ICAM-1 and Anti-VCAM-1 and analyzed by flow cytometry as fluorescence Histograms.

The Mean Fluorescence Intensity (MFI) of HBMECs treated with different stimuli was calculated.

IFN-gamma-induced HLA-DR was down-regulated in a dose-dependent manner by MP. High-dose MP reduced the TNF-alpha-induced ICAM-1 and VCAM-1 expression.

The down-regulation of Adhesion Molecules on Cerebral Endothelial Cells could decrease MonoNuclear Cell transmigration through the Blood-Brain Barrier and consequently the PeriVascular infiltrates.

The results add support to the rationale for high-dose MP treatment in Multiple Sclerosis relapses.


Cardiac Repolarization Abnormalities In Multiple Sclerosis: Spinal Cord MRI Correlates

de Seze J, Stojkovic T, Gauvrit JY, Saint Michel T, Ayachi M, Pruvo JP, Vermersch P
Muscle Nerve 2000 Aug;23(8):1284-6
Hopital R. Salengro, Dept of Neurology, CHRU de Lille, France
PMID# 10918270; UI# 20379344

Ventricular repolarization dysfunction has recently been reported in Multiple Sclerosis (MS).

We evaluated Ventricular repolarization dysfunction in 52 MS patients and looked for a relationship between corrected QT (QTc) abnormalities (i.e., abnormalities of QT intervals corrected for rate) and Spinal Cord Magnetic Resonance Imaging (MRI) findings.

QTc intervals were increased in MS patients compared with controls (P < 0.01) and were correlated with a reduction of Spinal Cord area (P < 0.01).

QTc abnormalities in MS were thus associated with Axonal loss, reflected by Spinal Cord Atrophy, rather than DeMyelination.

Copyright 2000 John Wiley & Sons, Inc.


Tumor Necrosis Factor-alpha Has Few Morphological Effects Within The Dorsal Columns Of The Spinal Cord, In Contrast To Its Effects In The Peripheral Nervous System

Hall SM, Redford EJ, Smith KJ
J NeuroImmunol 2000 Jul 1;106(1-2):130-136
NeuroInflammation Research Group, Division of Anatomy, Cell and Human Biology, Guy's, King's and St. Thomas' Schools of Medicine, Dentistry and Biomedical Sciences, Hodgkin Building, Guy's Campus, London, UK
PMID# 10814790

There is circumstantial evidence implicating the Pro-Inflammatory Cytokine Tumor Necrosis Factor (TNF) in the PathoGenesis of Multiple Sclerosis (MS), but there is no direct evidence that TNF can produce DeMyelination in the Central Nervous System (CNS).

We demonstrate here that single injections of TNF into the Dorsal Columns of adult rats produced a mild Inflammatory response indistinguishable from that seen in control Cords, but did not induce DeMyelination.

A similar response was seen when TNF-alpha was injected into Dorsal Columns where Central Axons had been ReMyelinated by Schwann cells.

In marked contrast, single IntraNeural injections of TNF into Sciatic Nerves produced acute changes in the EndoNeurial MicroVascular bed that were followed by DeMyelination and degeneration.


Physiologic And Functional Responses Of MS Patients To Body Cooling

Ku YT, Montgomery LD, Lee HC, Luna B, Webbon BW
Am J Phys Med Rehabil 2000 Sep-Oct;79(5):427-34
Lockheed Martin Engineering & Sciences, Moffett Field, California, USA
PMID# 10994884; UI# 20448350

The objective of this study was to compare the responses of Multiple Sclerosis (MS) patients to short-term cooling therapy using three different vest configurations.

Each garment was used to cool 13 male and 13 female MS subjects (31-67 yr). Oral and right and left ear temperatures were logged manually every 5 min.

Arm, leg, chest, and rectal temperatures, heart rate, and respiration were recorded continuously on a Biolog ambulatory monitor.

Each subject was given a series of subjective and objective evaluation tests before and after cooling.

The Life Enhancement Technologies and Steele vests test groups had similar, significant (P < 0.01) cooling effects on oral and ear canal temperatures, which decreased approximately 0.4 degrees C and 0.3 degrees C, respectively.

The Life Enhancement Technologies active liquid cooling vest produced the coldest (P < 0.01) skin temperature and provided the most improvement on subjective and objective performance measures.

These results show that the various garment configurations tested do not produce similar thermal responses in all MS patients.

The circulating liquid cooling vest was found to be more effective than either of the two passive cooling garments tested.


Intramuscular Interferon-ß-1a Therapy Initiated During A First DeMyelinating Event In Multiple Sclerosis

Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS)
Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW
N Engl J Med 2000 Sep 28;343(13):898-904
Buffalo General Hospital, Dept of Neurology, 100 High St., Buffalo, NY 14203
PMID# 11006365

Treatment with Interferon-ß has been shown to help patients with established Multiple Sclerosis, but it is not known whether initiating treatment at the time of a first clinical DeMyelinating event is of value.

We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical DeMyelinating event (Optic Neuritis, incomplete Transverse Myelitis, or a BrainStem or Cerebellar Syndrome) and evidence of prior subclinical DeMyelination on Magnetic Resonance Imaging (MRI) of the Brain.

After initial treatment with CorticoSteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of Interferon-ß-1a and 190 were assigned to receive weekly injections of placebo.

The study end points were the development of Clinically Definite Multiple Sclerosis and changes in findings on MRI of the Brain. The trial was stopped after a preplanned interim efficacy analysis.

During three years of follow-up, the cumulative probability of the development of Clinically Definite Multiple Sclerosis was significantly lower in the Interferon-ß-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002).

As compared with the patients in the placebo group, patients in the Interferon-ß-1a group had a relative reduction in the volume of Brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer Gadolinium-enhancing lesions (P<0.001) at 18 months.

Initiating treatment with Interferon-ß-1a at the time of a first DeMyelinating event is beneficial for patients with Brain lesions on MRI that indicate a high risk of Clinically Definite Multiple Sclerosis.


Genetics Of Multiple Sclerosis

Fukazawa T, Sasaki H, Kikuchi S, Hamada T, Tashiro K
Biomed Pharmacother 2000 Mar;54(2):103-6
Hokuyukai Neurology Hospital, Sapporo, Japan
PMID#10759295; UI# 20221045

Multiple Sclerosis (MS) is a Chronic Inflammatory DeMyelinating Disease of the Central Nervous System.

Although environmental risk factors are clearly involved in MS, the importance of Genetic factors has been strongly supported by the results of studies on multiplex families, though a weak association with Major Histocompatibility Complex (MHC) has been the only Genetic feature of MS consistently observed to date.

Other candidates Genes have been pointed out, but none has been confirmed. Recent Genome scans suggest that no single MS susceptibility locus is necessary or sufficient to cause MS, and this finding is compatible with a PolyGenic Etiology.

Furthermore, MS is a heterogeneous disorder, and thus different Genes may influence its course or presentation. Actually, some candidate Genes have been proposed, which contribute to the Genotype-phenotype interactions in MS.


Multiple Sclerosis Is Associated With An Imbalance Between Tumor Necrosis Factor-alpha (TNF-alpha)- And IL-10-Secreting Blood Cells That Is Corrected By Interferon-beta (IFN-ß) Treatment

Ozenci V, Kouwenhoven M, Huang Y, Kivisakk P, Link H
Clin Exp Immunol 2000 Apr;120(1):147-53
Karolinska Institutet, Division of Neurology, Unit of NeuroImmunology, Huddinge Univ Hospital, Stockholm, Sweden
PMID#10759776; UI# 20224075

The up-regulated B-Cell responses detectable in CerebroSpinal Fluid (CSF) and the augmented Myelin Antigen-specific T-Cell responses observed in the CSF as well as systematically in patients with Multiple Sclerosis (MS) suggest the involvement of Cytokines in disease development and perpetuation.

Here we report on the parallel involvement of TNF-alpha, IL-6, IFN-gamma and IL-10 in MS and controls, using Enzyme-Linked Immunospot (ELISPOT) assays to detect and enumerate Cytokine-secreting MonoNuclear Cells (MNC) prepared from blood and, for IL-6 and IL-10, from CSF without in vitro stimulation.

MS is associated with elevated levels of TNF-alpha-secreting blood MNC when compared with levels in groups of control patients with Myasthenia Gravis (MG) and Other Neurological Diseases (OND) or healthy subjects.

This elevation was confined to patients with untreated MS and not present in those examined during ongoing treatment with IFN-ß. Untreated patients with MS had lower numbers of IL-10-secreting blood MNC compared with the three control groups.

In patients undergoing treatment with IFN-ß, numbers of IL-10-secreting cells were in the same range as in controls.

Normalization of TNF-alpha from elevated, and of IL-10 from decreased levels could be one reason for the beneficial effects of IFN-ß in MS, although it remains to be shown whether these changes reflect phenomena primarily involved in MS PathoGenesis or secondary changes.

In CSF, levels of IL-10-secreting cells were higher than in blood in both MS and OND, with no difference between these groups.

Systemic aberrations of IL-6 and IFN-gamma and of IL-6 in CSF in MS versus controls were only minor, irrespective of treatment with IFN-ß.


Diagnostic Usefullness Of OligoClonal ImmunoGlobulin G bands In CerebroSpinal Fluid Using Isoelectric Focusing In Early Diagnosis Of Multiple Sclerosis

Caudie C, Allauzen O, Bancel J, Later R
Ann Biol Clin (Paris) 2000 Mar;58(2):187-193
Hopital Neurologique et NeuroChirurgical Pierre-Wertheimer, Laboratoire d'Immunologie et de Neuro-Immunologie, 59, boulevard Pinel, 69394 Lyon cedex 03
PMID# 10760705

A retrospective study was carried out at the Neurological and NeuroSurgical Hospital of Lyon in order to evaluate the interest of detecting IgG OligoClonal Bands by isoelectric focusing with IgG ImmunoRevelation for the early diagnosis of Multiple Sclerosis (MS).

Patients have been grouped according to their disorders: Multiple Sclerosis (281 cases), definite (182 cases) and possible (99 cases), Others Inflammatory Neurological diseases (63 cases), various Non-Inflammatory Neurological Disorders (180 cases) and indefined Neurological Disorders (664 cases).

The following examinations were performed: CSF cell count and Cytology after concentration and CytoCentrifugation, CSF and Serum determination of Albumin and IgG with CSF/Serum ratios, Agarose Gel Electrophoresis and Isoelectric focusing of OligoClonal IgG.

The technique used was isoelectric focusing using agarose gel, transfer onto PVDF membrane and then IgG ImmunoRevelation with biotinylated anti-human IgG AntiBodies. Isoelectric focusing with IgG ImmunoRevelation is the most sensitive (94%) and specific (96%) technique.

Isoelectric focusing with Immune detection can be recommended as the most efficient test (gold standard) for the detection of Chronic CNS Inflammation.

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