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MS Abstracts 4a-2g


  1. Inhibition of Experimental Allergic EncephaloMyelitis with an AntiBody that recognizes a novel Antigen expressed on Lymphocytes, Endothelial Cells, and Microglia
    Lab Invest 2000 Mar;80(3):313-26

  2. Association of a MyeloPeroxidase promoter polymorphism with Multiple Sclerosis
    J NeuroImmunol Suppl 2000 Jun 26;105(2):189-194

  3. Genetic variation in the B7-1 Gene in Multiple Sclerosis
    J NeuroImmunol Suppl 2000 Jun 26;105(2):184-188

  4. Modulation of Fas-Ligand (Fas-L) on human Microglial Cells: an in vitro study
    J NeuroImmunol Suppl 2000 Jun 26;105(2):109-114

  5. Th2 Immune regulation induced by T-Cell vaccination in Multiple Sclerosis
    Eur J Immunol 2000 Mar;30(3):908-13

  6. Quality of life and Multiple Sclerosis: validation of the French version of the MSQOF self-questionnaire (SEP-59)
    Rev Neurol (Paris) 2000;156(3):247-263

  7. The complexicity of Cytokine treatment in ongoing EAE induced with MBP Peptide 68-86 in Lewis rats
    Clin Immunol 2000 Apr;95(1 Pt 1):70-8

  8. InterLeukin-2 Gene deletion produces a robust reduction in susceptibility to Experimental AutoImmune EncephaloMyelitis in C57BL/6 mice
    NeuroSci Lett 2000 May 5;285(1):66-70

  9. Correlating Magnetic Resonance Imaging markers of Axonal injury and DeMyelination in motor impairment secondary to Stroke and Multiple Sclerosis
    Magn Reson Imaging 2000 May;18(4):369-78





#1

Inhibition Of Experimental Allergic EncephaloMyelitis With An AntiBody that Recognizes A Novel Antigen Expressed On Lymphocytes, Endothelial Cells, And Microglia

Williams KC, Zhao W, Politopoulou G, Male D, Hickey WF
Lab Invest 2000 Mar;80(3):313-26
Harvard Medical School, Division of Comparative Pathology, New England Regional Primate Research Center, Southborough, Massachusetts 01772, USA
PMID# 10744067; UI# 20205934
Abstract

Experimental Allergic EncephaloMyelitis (EAE) is a frequently employed animal model of the human disease Multiple Sclerosis. EAE can be induced by adoptive transfer of CD4+ T-Cells that are specific for Central Nervous System (CNS) Antigens, typically Myelin proteins.

Although the Pathogenic mechanism or mechanisms responsible for the clinical signs and histological changes in EAE and Multiple Sclerosis are not fully defined, the entry of T-Lymphocytes and Antigen recognition within the CNS are required.

The present study describes the participation of a novel cell surface molecule with properties suggesting a role in cell-cell adhesion or co-stimulation, or both, in the development of EAE in the rat.

The molecule is defined by the unique MonoClonal AntiBody (mAb) TLD-4A2. The TLD-4A2 Antigen is present on resting and activated T-Lymphocytes, activated CNS Endothelial Cells, and Microglia.

The Antigen is normally distributed in many tissues including Lymph Node, Thymus, and Spleen, as well as in the inflamed CNS. Both its pattern of tissue distribution and ImmunoPrecipitation and ImmunoBlotting studies suggest that the TLD-4A2 Antigen is a novel molecule.

Treatment of rats with the purified 4A2 mAb resulted in the inhibition of the clinical signs of EAE and also decreased the number T-Cells and Macrophages accumulating in the CNS Parenchyma.

TLD-4A2 AntiBody did not seem to directly interfere with T-Cell viability in vivo, as demonstrated by the ability to recover and stimulate CD4+ Encephalitogenic T-Cells from Cervical Lymph Nodes of 4A2-treated animals. In vitro, the AntiBody partially blocked T-Cell proliferation assays.

These data suggest that the TLD-4A2 mAb recognizes a novel molecule expressed on Lymphocytes, Endothelial Cells, and MMacrophages that may play a role in hematogenous cell traffic and the initiation of CNS inflammation.



#2

Association Of A MyeloPerOxidase ProMoter PolyMorphism With Multiple Sclerosis

Kantarci OH, Atkinson EJ, Hebrink DD, McMurray CT, Weinshenker BG
J NeuroImmunol Suppl 2000 Jun 26;105(2):189-194
Mayo Clinic and Foundation, Dept of Neurology, 200 First Street, SW, Rochester, MN, USA
PMID# 10742562
Abstract

MyeloPerOxidase (MPO) generates Hypochlorous Acid and other reactive Oxygen intermediates leading to tissue damage.

MPO is expressed in Macrophages-Microglia in Multiple Sclerosis (MS) lesions. A G-->A substitution that abolishes an SP1 transcription factor consensus sequence in the promoter reduces Gene expression.

We studied the association of the Genetic variant with MS. We did not find an association with gender, age at onset, susceptibility to, or the course and severity of MS in a population-based sample of 122 patients from Olmsted County.



#3

Genetic Variation In The B7-1 Gene In Multiple Sclerosis

Weinshenker BG, Hebrink DD, Klein C, Atkinson EJ, O'Brien PC, McMurray CT
J NeuroImmunol Suppl 2000 Jun 26;105(2):184-188
Mayo Clinic and Mayo Foundation, Dept of Neurology, 200 First St. SW, Rochester, MN, USA
PMID# 10742561
Abstract

Co-stimulation of T-Cells by B7-1, a protein that is expressed on Antigen-Presenting Cells, favors a T-Helper Type1 (Th1) Cellular Response. Th1/Th2 bias may influence disease susceptibility or course of MS.

We screened the entire coding sequence as well as the 5'- and 3'-untranslated regions of the B7-1 Gene using a mutation scanning technique, DideoxyFingerprinting, in DNA from 111 patients with MS from Olmsted County, Minnesota. We identified five Genetic variants.

None alter protein structure nor have apparent functional significance. Selected variants of sufficient frequency were tested for an association with course and severity of MS and one was tested for an association with susceptibility; none of the association tests were positive.



#4

Modulation Of Fas-Ligand (Fas-L) On Human Microglial Cells: An In Vitro Study

Frigerio S, Silei V, Ciusani E, Massa G, Lauro GM, Salmaggi A
J NeuroImmunol Suppl 2000 Jun 26;105(2):109-114
Istituto Nazionale Neurologico 'C. Besta', Via Celoria 11, 20133, Milan, Italy
PMID# 10742551
Abstract

The expression of Fas-Ligand (Fas-L) on Microglia could be relevant in Multiple Sclerosis ImmunoPathology.

The present study was performed to evaluate in vitro the expression of Fas-L in human Microglial Cells both unstimulated and after stimulation with IFN-γ, ß-IFN-1b and ß-IFN-1b+IFN-γ.

Cells were stimulated for 6,12, 24 and 48 h. Surface Fas-L was evaluated by flow cytometry, total Fas-L by Western blot, whereas mRNA for Fas-L was measured by RT-PCR. We also evaluated the capacity of Microglial Cells to induce, in vitro, Apoptosis on Fas-positive T-Leukemia Jurkat Cells.

Our results showed a constitutive expression of Fas-L on Microglia. IFN-γ downregulated the expression of the molecule, while ß-IFN-1b and ß-IFN-1b+IFN-γ did not.

The amount of surface Fas-L was related to the ability of Microglial Cells to induce Apoptosis in Fas-positive targeT-Cells, which was partly inhibited by blockade of the Fas-Fas-L pathway.



#5

Th2 Immune Regulation Induced By T-Cell Vaccination In Multiple Sclerosis

Zang YC, Hong J, Tejada-Simon MV, Li S, Rivera VM, Killian JM, Zhang JZ
Eur J Immunol 2000 Mar;30(3):908-13
Baylor College of Medicine, Multiple Sclerosis Research Laboratory, Dept of Neurology, Houston 77030, USA
PMID# 10741408; UI# 20203449
Abstract

T-Cell responses to Myelin Basic Protein (MBP) are potentially involved in the PathoGenesis of Multiple Sclerosis (MS).

In this study, we demonstrated that subcutaneous inoculations with irradiated autologous MBP-reactive T-Cell clones (T-Cell Vaccination) elicited CD8+ anti-idiotypic T-Cell responses and CD4+ Th2 Cell responses in patients with MS.

Both regulatory cell types induced by T-Cell Vaccination contributed to the inhibition of MBP-reactive T-Cells while they differed in the recognition pattern and functional properties.

We describe for the first time that the Th2 regulatory cells reacted with activated but not resting T-Cells in the context of MHC Class II molecules and inhibited the proliferation of MBP-reactive T-Cells through the secretion of IL-4 and IL-10.

The T-T-Cell interaction mediated by Th2 regulatory cells was independent of the Antigen specificity of activated T-Cells.

The findings have important implications for our understanding of the regulatory mechanism induced by T-Cell Vaccination.



#6

Quality Of Life And Multiple Sclerosis: Validation Of The French Version Of The MSQOF Self-Questionnaire (SEP-59)

Vernay D, Gerbaud L, Biolay S, Coste J, Debourse J, Aufauvre D, Beneton C, Colamarino R, Glanddier PY, Dordain G, Clavelou P
Rev Neurol (Paris) 2000;156(3):247-263
Federation de Neurologie

PMID# 10740096
Abstract

We conducted a prospective study among 166 Multiple Sclerosis (MS) patients (103 from an university hospital, 63 from a MS rehabilitation center) to assess the properties of the French version of the Multiple Sclerosis Quality Of Life - 54 items (MS QOL-54) which combines the MOS SF36 together with MS specific items.

The SF-36 had been translated into French through the IQOLA project. We translated and adapted the MS specific items with the help of three different teams.

The translation into French has an addition of five items, because we kept the MS specific items of an earlier unpublished form. Acceptability is excellent with a response rate over 90p.100.

Test-retest reliability is good except for the "role limitation-emotional" scale of the SF-36. Construct validity, based on factor analysis, shows no change in the SF-36 internal consistency and the specific items provided their own information.

External validity, tested against both medical (Expanded Disability Status Scale, Kurtzke scale, Mini-Mental-State and disease stage) and rehabilitation (Functional Independence Measure) parameters is excellent.

The French MS QOL questionnaire contains 59 items including both the SF-36 and the MS QOL-54 items. This will permit international comparisons of MS patients' care and therapy.



#7

The Complexicity Of Cytokine Treatment In Ongoing EAE Induced With MBP Peptide 68-86 In Lewis Rats

Xu LY, Ishikawa M, Huang YM, Levi M, van der Meide PH, Wahren B, Link H, Xiao BG
Clin Immunol 2000 Apr;95(1 Pt 1):70-8
Karolinska Institute, Division of Neurology, Huddinge Univ Hospital, Stockholm, Sweden
PMID# 10794434; UI# 20252408
Abstract

IL-10 and TGF-ß1 are important ImmunoRegulatory Cytokines associated with clinical remissions in Multiple Sclerosis and amelioration of Experimental Allergic EncephaloMyelitis (EAE).

IL-10 and TGF-ß1 have previously been shown to prevent the development of EAE. Here, we study effects of IL-10 and TGF-ß1 in ongoing EAE.

When IL-10 or TGF-ß1 was administered by the nasal route from day 0 to day 7 postimmunization (pi), both IL-10 and TGF-ß1 prevented the development of acute EAE in Lewis rats.

When IL-10 or TGF-ß1 was administered by the nasal route from day 5 to day 12 pi, both IL-10 and TGF-ß1 failed to influence clinical EAE.

The inhibition of clinical EAE severity in IL-10-prevented rats was associated with reduced proliferation, IFN-γ mRNA expression, and IFN-γ secretion, while proliferation as well as IFN-γ mRNA expression and secretion were augmented in TGF-ß1-prevented rats.

TGF-ß1-prevented rats exhibited high levels of NO production by DC, which may mediate Apoptosis of CD4+ T-Cells and of the DC themselves.

For prevention, both IL-10 and TGF-ß1 inhibited infiltration of CD4+ T-Cells within the CNS, but neither IL-10 nor TGF-ß1 induced Immune deviation from Th1 to Th2.

Expression of IL-4 mRNA was not altered in IL-10- and TGF-ß1-prevented rats. These results demonstrate that IL-10 and TGF-ß administration by the nasal route can prevent the development of acute EAE, but by different mechanisms.

The findings in rats with ongoing EAE have implications for the clinical application of Cytokine treatment in AutoImmune Diseases.



#8

InterLeukin-2 Gene Deletion Produces A Robust Reduction In Susceptibility To Experimental AutoImmune EncephaloMyelitis In C57BL/6 Mice

Petitto JM, Streit WJ, Huang Z, Butfiloski E, Schiffenbauer J
NeuroSci Lett 2000 May 5;285(1):66-70
UF Brain Institute, Dept of Psychiatry, Box 100256,
Univ of Florida College of Medicine, Gainesville, USA
PMID# 10788709
Abstract

Dysregulation of InterLeukin-2 (IL-2), the prototypical T-Cell growth factor and ImmunoRegulatory Cytokine, may modify self-tolerance and predisposition to AutoImmunity.

The available literature suggested that IL-2 could be hypothesized to either propagate or inhibit the development AutoImmune DeMyelinating Disorders of the Central Nervous System such as Multiple Sclerosis.

Thus, the present study sought to test these competing hypotheses by examining whether disrupting one or both IL-2 Gene Alleles would render mice more or less vulnerable to Experimental AutoImmune EncephaloMyelitis (EAE).

Myelin Oligodendrocyte Glycoprotein was used to induce EAE in C57BL/6-IL-2(-/-) knockout, C57BL/6-IL-2(+/-) heterozygote and C57BL/6-IL-2(+/+) wild-type mice.

All of the wild-type and heterozygote mice developed signs of EAE compared with only 23% of the IL-2 knockout mice.

HistoPathological examination of Lumbar Spinal Cord sections confirmed that SubPial PeriVascular inflammatory infiltrates found in wild-type and heterozygote mice were absent in the unaffected IL-2 knockout mice.

These data demonstrate that vulnerability to EAE is markedly reduced in C57BL/6 mice lacking IL-2, and suggest that this Cytokine may play a critical role in AutoImmune processes of the Central Nervous System.



#9

Correlating Magnetic Resonance Imaging Markers Of Axonal Injury And DeMyelination In Motor Impairment Secondary To Stroke And Multiple Sclerosis

Pendleburyab ST, Lee MA, Blamire AM, Styles P, Matthews PM
Magn Reson Imaging 2000 May;18(4):369-78
Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), John Radcliffe Hospital, Oxford, UK
PMID# 10788713; UI# 20251109
Abstract

The primary pathological mechanisms in Stroke and Multiple Sclerosis (MS) are very different but in both diseases, Impairment may arise from a final common pathway of Axonal damage.

We aimed to examine the relationship between motor impairment, Magnetization Transfer Ratio (MTR) (an index of DeMyelination), and N-AcetylAspartate (NAA) loss (an index of Axonal Injury) localized to the Descending Motor Pathways in Stroke and MS.

Twelve patients between 1 and 10 months after first ischaemic Stroke causing a Motor Deficit and 12 patients with stable MS with asymmetric Motor Deficit were examined.

T2-weighted imaging of the Brain together with MTR and proton (Voxel (volume element) 1.5 x 2 x 2 cm(3)) MRS localized to the Posterior Limb of the Internal Capsule were performed and correlated to a composite Motor Deficit score.

MTR and NAA in the Internal Capsule were reduced in both Stroke and MS patients compared to controls. NAA loss correlated with Motor Deficit score in both Stroke and MS (p < 0.001 and p = 0.04, respectively).

Correlations were seen between MTR and Motor Deficit (p < 0.001) MTR and NAA loss (p < 0.001) in Stroke patients but not in MS patients.

Axonal injury in the descending motor tracts would appear to be an important determinant of motor impairment in both Stroke and MS.

In Stroke, MTR measures of DeMyelination are closely related to Axonal damage and thus also correlate with Motor Deficit.

However in MS, MTR measures of DeMyelination do not correlate with NAA loss or motor deficit suggesting that DeMyelination and Gliosis may occur independently of Axonal damage and are less closely linked with functional impairment.



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