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MS Abstracts 8c-2g

  1. Extended observations on MS patients treated with IM Interferon-ß-1a (Avonex): implications for modern MS trials and therapeutics
    J NeuroImmunol 2000 Jul 24;107(2):167-173

  2. NeuroProtective effect of Inflammation: implications for the therapy of Multiple Sclerosis
    J NeuroImmunol 2000 Jul 24;107(2):161-166

  3. T-Cell vaccination in Secondary/Progressive Multiple Sclerosis
    J NeuroImmunol 2000 Jul 24;107(2):130-139

  4. Evidence for a role of gammadelta T-Cells in DeMyelinating Diseases as determined by activation states and responses to lipid Antigens
    J NeuroImmunol 2000 Jul 24;107(2):124-129

  5. Theiler's Murine EncephaloMyelitis Virus induces rapid Necrosis and delayed Apoptosis in Myelinated mouse Cerebellar explant cultures
    Brain Res 2000 Jun 23;868(2):259-267

  6. The role of B-Cells and AutoAntiBodies in Multiple Sclerosis
    Ann Neurol 2000 Jun;47(6):694-706

  7. CC-Chemokine receptor 5 PolyMorphism and age of onset in familial Multiple Sclerosis. Multiple Sclerosis Genetics Group
    Immunogenetics 2000 Apr;51(4-5):281-8

  8. Wavelet decomposition of the Blink Reflex R2 component enables improved discrimination of Multiple Sclerosis
    Clin NeuroPhysiol 2000 May 1;111(5):810-820

  9. HyperProlactinemia in Optico-Spinal Multiple Sclerosis
    Intern Med 2000 Apr;39(4):296-9


Extended Observations On MS Patients Treated With IM Interferon-ß-1a (Avonex): Implications For Modern MS Trials And Therapeutics

Jacobs L, Rudick R, Simon J
J NeuroImmunol 2000 Jul 24;107(2):167-173
State Univ of New York at Buffalo, Dept of Neurology, Buffalo General Hospital, 100 High Street, 14203, Buffalo, NY, USA

Extended observations of the pivotal Phase III clinical trial of Interferon-beta-1a (IFN-ß-1a; Avonex, Biogen) in Relapsing MS patients revealed that:

  1. Active treatment significantly slowed the accumulation of physical disability over time, reduced clinical exacerbations and MRI Brain lesions

  2. Clinical efficacy did not depend on Disability endpoints

  3. Active treatment benefited multiple MRI measures of Brain Lesions

  4. Cerebral Atrophy occurred over 2 years in relatively mildly disabled patients

  5. Avonex could slow the development of Atrophy after the first year of treatment.

Data from this study were recently used to design a new outcome measure for MS clinical trials (The Multiple Sclerosis Functional Composite), and was also the basis for two ongoing studies of IFN-ß-1a: one in patients with MonoSymptomatic onset of MS and the other in Secondary/Progressive MS.


NeuroProtective Effect Of Inflammation: Implications For The Therapy Of Multiple Sclerosis

Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H
J NeuroImmunol 2000 Jul 24;107(2):161-166
Institute for Clinical NeuroImmunology and Dept of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistrasse 15, D-81366, Munich, Germany
PMID# 10854651

AutoReactive T-Cells are a component of the normal Immune System. It has been proposed that some of these AutoReactive T-Cells even have a protective function.

Recent studies support this notion by demonstrating that:

  1. Myelin Basic-Protein (MBP-) specific T-Cells show NeuroProtective effects in vivo

  2. Activated Antigen-specific human T-Cells and other Immune Cells produce bioactive Brain-Derived NeuroTrophic Factor (BDNF) in vitro

  3. BDNF is expressed in different types of Inflammatory Cells in Brain lesions of patients with Acute Disseminated LeukoEncephalopathy or Multiple Sclerosis.

We postulate that the NeuroProtective effect of T-Cells and other Immune Cells observed in vivo is at least partially mediated by BDNF and other NeuroTrophic Factors.

The concept of NeuroProtective AutoImmunity has obvious implications for the therapy of Multiple Sclerosis and other NeuroImmunological Diseases.


T-Cell Vaccination In Secondary/Progressive Multiple Sclerosis

Correale J, Lund B, McMillan M, Ko DY, McCarthy K, Weiner LP
J NeuroImmunol 2000 Jul 24;107(2):130-139
USC School of Medicine, Dept of Neurology, 1333 San Pablo Street, MCK 142, 90033, Los Angeles, CA, USA

Four Secondary/Progressive MS patients were vaccinated with bovine Myelin-reactive irradiated T-Cell lines from their peripheral blood.

Patients were followed for 30-39 months, and monitored for Immunological responses toward the vaccine, and for their clinical characteristics.

Two patients showed stable EDSS score over time, one patient showed improvement by one EDSS step, and in the remaining patient her EDSS advanced over time.

After the second inoculation there was a progressive decline of circulating whole Myelin-reactive T-Cells, MBP143-168, PLP104-117, and MOG43-55-peptide-reactive T-Cells.

In contrast the frequency of Tetanus toxoid-reactive T-Cells remained unchanged. T-Cell Vaccination (TCV) was also associated with a decline of Myelin-specific IL-2- and IFN-gamma-secreting T-Cells.

Twelve T-Cell Lines (TCL) that recognize the inoculates were isolated from the peripheral blood of two patients. Ten of these TCL were CD8+ and Lysed the inoculates in a MHC Class I restricted manner.

The remaining two TCL were CD4+, and Lysed the inoculates by MHC Class II restricted Cytolytic activity.

All T-Cell Lines lysed not only Myelin-reactive T-Cells, but also TCL specific for MBP143-168, PLP104-117 and MOG43-55 Peptides. Control TCL specific for Tetanus toxoid were not lysed.

Neutralizing anti-Fas mAb did not influence the killing. Moreover, culture supernatants from two TCL which produce IL-10, were able to block the proliferation of Myelin protein-specific TCL. This effect was abrogated using mAbs specific for IL-10.

The data obtained indicated that TCV using autologous irradiated bovine Myelin-reactive T-Cells promotes an effective depletion of T-Cells reactive against different Myelin Antigens.


Evidence For A Role Of gammadelta T-Cells In DeMyelinating Diseases As Determined By Activation States And Responses To Lipid Antigens

Borsellino G, Koul O, Placido R, Tramonti D, Luchetti S, Galgani S, Salvetti M, Gasperini C, Ristori G, Bonetti B, Bach S, Cipriani B, Battistini L
J NeuroImmunol 2000 Jul 24;107(2):124-129
Laboratory of NeuroImmunology, IRCCS Santa Lucia, Via Ardeatina, 306, 00179, Rome, Italy

In this report we review current information on the phenotypic and functional properties of gammadelta T-Cells in DeMyelinating Disorders.

The results support the conclusion that although gammadelta T-Cells show evidence of activation in patients with either Multiple Sclerosis (MS) or Guillain Barre Syndrome (GBS), differences exist in the phenotypic and functional properties of these cells between the two diseases.

In particular, our data indicate that in patients with MS the Vdelta2 subset is activated and that these cells can be induced to secrete high levels of ProInflammatory Cytokines.

In contrast, in patients with GBS, the Vdelta1 subset is expanded and can be induced to secrete Cytokines more associated with a Humoral Response.


Theiler's Murine EncephaloMyelitis Virus Induces Rapid Necrosis And Delayed Apoptosis In Myelinated Mouse Cerebellar Explant Cultures

Anderson12 R, Harting2 E, Frey MS, Leibowitz3 JL, Miranda3 RC
Brain Res 2000 Jun 23;868(2):259-267
Texas A&M UnivHealth Science Center, Dept of Human Anatomy, 228 Reynolds Medical Bldg., 77843-1114, College Station, TX, USA

Infection with the Daniel strain of Theiler's Murine EncephaloMyelitis (TMEV-DA) Virus induces persistent DeMyelinating lesions in mice and serves as a model for Multiple Sclerosis.

During the acute phase of the disease, however, Viral infection leads to cell death in vivo. Viral-induced death may result directly from Viral infection of Neural Cells, or indirectly, by activation of the Immune System.

To examine the direct effects of TMEV infection on Neural Cells, Myelinated explant cultures of the murine Cerebellum were infected with 10(5) pfu of TMEV-DA for periods ranging from 1 to 72 h.

Our results indicate that TMEV-DA replicates in cultured Neural tissue. Initially, Viral Antigen is localized to a few isolated Neural Cells.

However, within 72 h Antigen was observed in multiple Foci that included damaged cells and ExtraCellular debris.

Viral infection led to a rapid and cyclical induction of Necrosis with a time period that was consistent with the Lytic phase of the Viral life-cycle. Simultaneously, we observed an increase in Apoptosis 48 h post-infection.

Electron micrographic analysis indicated that Viral-infected cultures contained cells with fragmented Nuclei and condensed CytoPlasm, characteristic of Apoptosis.

The localization of Apoptosis to the Cerebellar Granule Cell Layer, identified these cells as presumptive Granule Neurons. Viral infection, however, did not lead to Myelin damage, though damaged Axons were visible in TMEV-infected cultures.

These results suggest that during the acute phase of infection, TMEV targets Neural Cells for Apoptosis without directly disrupting Myelin. Myelin damage may therefore result from the activation of the Immune System.


The Role Of B-Cells And AutoAntiBodies In Multiple Sclerosis

Archelos JJ, Storch MK, Hartung HP
Ann Neurol 2000 Jun;47(6):694-706
Karl-Franzens-Universitat, Dept of Neurology, Graz, Austria
PMID#10852535; UI# 20309375

A variety of Cellular and Humoral Immunological abnormalities have been observed in Multiple Sclerosis (MS).

In the past few years, several lines of evidence converged to imply an important role of AutoReactive AntiBodies and B-Cells in the PathoGenesis of MS.

Recent data suggest that AutoAntiBodies may be harmful in Lesion formation but also potentially beneficial in repair.

This review surveys recent advances in the concepts of generation and nature of PathoGenetic AutoAntiBodies, their potential modes of action, mechanisms of their long-term persistence, and the role of the inflamed Brain tissue as a B-Cell-supporting MicroEnvironment in MS.

Based on the presence of specific AutoAntiBodies, it seems possible to define distinct MS subgroups in the near future. The therapeutic relevance of these new findings is presented.


CC-Chemokine Receptor 5 PolyMorphism And Age Of Onset In Familial Multiple Sclerosis. Multiple Sclerosis Genetics Group

Barcellos LF, Schito AM, Rimmler JB, Vittinghoff E, Shih A, Lincoln R, Callier S, Elkins MK, Goodkin DE, Haines JL, Pericak-Vance MA, Hauser SL, Oksenberg JR
Immunogenetics 2000 Apr;51(4-5):281-8
Univ of California at San Francisco, Dept of Neurology, 94143-0435, USA
PMID# 10803840; UI# 20260985

Multiple Sclerosis (MS) is a common disease of the Central Nervous System characterized by Myelin loss and Progressive Neurological Dysfunction.

An underlying Genetic susceptibility plays a clear role in the etiology of MS, likely acting in concert with an undefined environmental exposure.

Full-Genome screenings in multiplex MS families have identified several susceptibility regions, supporting a polygenic model for MS.

Among these regions, evidence for weak linkage was observed at 3p/3cen suggesting the presence of an MS Gene(s) of modest effect. Encoded here are two Chemokine receptors, CCR5 and CCR2B.

We examined the Chromosome 3p21-24 region in 125 MS families (322 total affecteds and 200 affected sib-pairs), and performed Genetic analyzes of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) using both linkage - and association-based tests.

No evidence of linkage to MS was observed for any of the tested markers. Affected relative-pair (SimIBD) and sib-pair analyzes (ASPEX), and association testing (sib-TDT) for each locus were also not significant.

However, age of onset was approximately 3 years later in patients carrying the CCR5delta32 deletion (P=0.018 after controlling for gender effects).

Thus, Chemokine receptor expression may be associated with differential disease onset in a subset of patients, and may provide a therapeutic target to modulate Inflammatory DeMyelination.


Wavelet Decomposition Of The Blink Reflex R2 Component Enables Improved Discrimination Of Multiple Sclerosis

Kumaran MS, Devasahayam SR, Sreedhar T
Clin NeuroPhysiol 2000 May 1;111(5):810-820
Indian Institute of Technology, School of Biomedical Engineering, Powai, Bombay, India
PMID# 10802451

The Blink Reflex R2 component was subjected to wavelet decomposition for time feature extraction in order to classify the functional status of patients with Multiple Sclerosis.

The Blink Reflex was recorded bilaterally with unilateral stimulation of the Supra-Orbital Nerve in 37 normal subjects and 9 patients with Multiple Sclerosis (MS).

The late component, R2, was subjected to time-frequency decomposition using the Daubechies-4 wavelet.

Using the time-frequency coefficients, the mean time of the R2 wave as well as the standard deviation of the R2 interval were calculated in each trial.

The wavelet transform enables noise reduction by allowing selective use of frequency bands with high signal-to-noise ratio for time feature extraction; therefore automatic estimation of time parameters is robust.

The distribution densities of the mean and the standard deviation of the R2 wave duration for the set of trials for each subject were computed.

An appreciable difference in the densities of the two parameters extracted in the wavelet domain was seen between normals and patients. This is in contrast to the onset latency of R2 which poorly discriminates MS patients from normals.

The results suggest that the mean and standard deviation of the R2-time robustly estimated using wavelet decomposition can be used to support clinical diagnosis in tracking the functional status of patients with diseases like Multiple Sclerosis.


HyperProlactinemia In Optico-Spinal Multiple Sclerosis

Yamasaki K, Horiuchi I, Minohara M, Osoegawa M, Kawano Y, Ohyagi Y, Yamada T, Kira J
Intern Med 2000 Apr;39(4):296-9
Neurological Institute, Dept of Neurology, and Kyushu University, Graduate School of Medical Sciences, Fukuoka
PMID# 10801143; UI# 20259081

To clarify the clinical features of MS patients with HyperProlactinemia.

Subjects And Methods
The Serum Prolactin level was measured in 67 Japanese patients (19 men and 48 women) with Multiple Sclerosis (MS) and in 16 patients (4 men and 12 women) with HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) using a two-site ImmunoRadiometric assay.

In the MS patients, 32 were classified as having Asian type MS showing a selective involvement of the Optic Nerves and Spinal Cord, while the other 35 were classified as having Western type MS which displayed Disseminated Central Nervous System involvement.

In women, the Serum Prolactin level was found to be significantly higher only in Asian type MS (mean=23.1 ng/ml, n=25) than in HAM/TSP (mean=6.9 ng/ml, n=12) (p=0.0297), while it did not differ significantly in men among the three groups.

HyperProlactinemia was significantly associated with acute relapse involving the Optic Nerves.

All MS patients with HyperProlactinemia (7 women with Asian type MS and 2 women with Western type MS) showed recurrent OpticoMyelitis either throughout or in the early course of the disease.

And also had a higher age of onset, a higher Expanded Disability Status Scale score, a greater Visual Impairment, and higher cell counts and protein contents in the CerebroSpinal Fluid than did the NormoProlactinemic patients.

HyperProlactinemia may be one of the characteristic features of Asian patients with MS who preferentially show the Optic Nerve involvement.

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