MS Abstracts 01a-2g1

  1. LPS/IFN-γ cytotoxicity in Oligodendroglial Cells: role of Nitric Oxide and protection by the anti-inflammatory Cytokine IL-10
    Eur J NeuroSci 2001 Feb;13(3):493-502

  2. Monocytes in Multiple Sclerosis: phenotype and Cytokine profile
    J NeuroImmunol 2001 Jan 1;112(1-2):197-205

  3. Regulation of Chemokine receptor CCR5 and production of RANTES and MIP-1alpha by Interferon-ß
    J NeuroImmunol 2001 Jan 1;112(1-2):174-180

  4. Immunomodulatory effects of Interferon-ß-1a in Multiple Sclerosis
    J NeuroImmunol 2001 Jan 1;112(1-2):153-162

  5. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation
    J NeuroImmunol 2001 Jan 1;112(1-2):146-152

  6. Relationship between Serum levels of IL-10, MRI activity and Interferon-ß-1a therapy in Relapsing/Remitting MS
    J NeuroImmunol 2001 Jan 1;112(1-2):139-145

  7. Polyclonal ImmunoGlobulins (IVIg) modulate Nitric Oxide production and Microglial functions in vitro via Fc receptors
    J NeuroImmunol 2001 Jan 1;112(1-2):63-71

  8. Induction of Nitric Oxide Synthase and activation of NF-kappaB by InterLeukin-12 p40 in Microglial cells
    J Biol Chem 2000 Dec 7

  9. Myelin Oligodendrocyte Glycoprotein-DNA vaccination induces AntiBody-mediated autoaggression in Experimental AutoImmune EncephaloMyelitis
    Eur J Immunol 2000 Dec;30(12):3663-3671

  10. T-Cell reactivity to multiple Myelin Antigens in Multiple Sclerosis and controls
    J NeuroSci Res 2001 Feb 1;63(3):290-302


LPS/IFN-γ Cytotoxicity In Oligodendroglial Cells: Role Of Nitric Oxide And Protection By The Anti-Inflammatory Cytokine IL-10

Molina-Holgado E, Vela JM, Arevalo-Martin A, Guaza C
Eur J NeuroSci 2001 Feb;13(3):493-502
Instituto Cajal, Neural Plasticity Unit, Consejo Superior de Investigaciones Cientificas, Avenida Doctor Arce 37, 28002 Madrid, Spain; Unitat d'Histologia, Dept de Biologia Cellular, Fisiologia i Immunologia, Facultad de Medicina, 08193 Bellaterra, Barcelona, Spain
PMID# 11168556

ProInflammatory mediators have been implicated in DeMyelinating Disorders, including Multiple Sclerosis.

Whereas it has been proposed that the AntiInflammatory Cytokines InterLeukins (IL-4) and IL-10 participate in disease recovery.

The present study analyzed the effect of Interferon-gamma (IFN-γ) and Bacterial Endotoxin LipoPolySaccharide, (LPS) on proliferation and survival of progenitors and differentiated Oligodendrocytes.

We also investigated the presence of receptors for IL-4 and IL-10 in Oligodendroglial Cells and explored a possible protective action of IL-4 and IL-10 in cultures following LPS/IFN-γ.

Finally, the role of endogenous Nitric Oxide (NO) on cell viability and the modulatory action of IL-4 and IL-10 on inducible Nitric Oxide Synthase (INOS) expression were also analyzed.

We report that LPS and/or IFN-γ reduced proliferation and viability of Oligodendroglial cells.

Cell death, presumably by Apoptosis as evidence by TUNEL and Annexin V binding, was observed following LPS/IFN-γ, progenitors being more sensitive than differentiated cells.

At both developmental stages, LPS/IFN-γ-treated cultures expressed iNOS protein and released micromolar concentrations of NO.

In progenitors, LPS/IFN-γ-mediated cell damage was partially dependent on endogenous NO production.

Whereas NO was fundamental for cytotoxicity of differentiated Oligodendrocytes.

Both cell types expressed mRNA for IL-4 and IL-10 Receptors and expression of IL-10 Receptors at the protein level was also demonstrated.

Treatment with either Cytokine inhibited the expression of INOS resulting from the ProInflammatory stimulation.

IL-10 was more effective than IL-4 in suppressing iNOS expression and, interestingly, IL-10 conferred protection against Oligodendroglial death evoked by LPS/IFN-γ.

Our data raise the question of whether IL-10 may play a protective role in DeMyelinating diseases.

Not only downregulating the function of inflammatory cells but also promoting survival of progenitors and differentiated Oligodendrocytes.


Monocytes In Multiple Sclerosis: Phenotype And Cytokine Profile

Kouwenhoven M, Teleshova N, Ozenci V, Press R, Link H
J NeuroImmunol 2001 Jan 1;112(1-2):197-205
Karolinska Institutet, Huddinge Univ Hospital, NeuroImmunology Unit, Division of Neurology, Stockholm, Sweden
PMID# 11108949

Multiple Sclerosis (MS) is an inflammatory DeMyelinating disease characterized by Immune abnormalities in the Central Nervous System (CNS) as well as systemically.

Activated, blood-borne Monocytes are abundant in MS lesions, the properties of circulating Monocytes are incompletely known.

To delineate phenotype and levels of Cytokine secreting Monocytes in MS patients' blood, ELISPOT assays were used for detection and enumeration of Monocytes secreting the Cytokines IL-6, IL-12, TNF-alpha and IL-10.

In parallel, the expression by Monocytes of co-stimulatory molecules (CD40, CD80, CD86), Major Histocompatibility Complex molecules (HLA-ABC, HLA-DR) and Fcgamma receptors (CD16, CD64) was examined by flow cytometry.

Levels of blood Monocytes secreting IL-6 and IL-12 were higher in patients with untreated MS and Other Neurological Diseases (OND) compared to healthy controls.

While levels of Monocytes secreting TNF-alpha and IL-10 did not differ between groups.

MS patients' blood Monocytes also displayed elevated mean fluorescence intensity for the co-stimulatory molecule CD86, and MS patients with longer disease duration (>10 years) and higher disease severity (EDSS >3) had higher percentages of CD80 expressing Monocytes.

Compared to patients with short duration or lower severity. In conclusion, Monocyte aberrations occur in MS and may change over the disease course.


Regulation Of Chemokine Receptor CCR5 And Production Of RANTES And MIP-1alpha By Interferon-ß

Zang YC, Halder JB, Samanta AK, Hong J, Rivera VM, Zhang JZ
J NeuroImmunol 2001 Jan 1;112(1-2):174-180
Baylor-Methodist Multiple Sclerosis Center, Multiple Sclerosis Research Laboratory, and Dept of Neurology
6501 Fannin Street, NB302, 77030, Houston, TX, USA
PMID# 11108946

Trafficking of inflammatory T-Cells into the Brain is associated with interactions of certain Chemokines with their receptors, which plays an important role in the PathoGenesis of Multiple Sclerosis (MS).

We examined whether Interferon-beta (IFN-ß) had the ability to regulate the production of Chemokines and the expression of their receptors in T-Cells derived from patients with MS.

It was demonstrated for the first time that in vitro exposure of T-Cells to IFN-ß-1a selectively inhibited mRNA expression for RANTES and MIP-1alpha and their receptor CCR5.

T-Cell surface expression of CCR5 was significantly reduced in MS patients treated with IFN-ß, correlating with decreased T-Cell transmigration toward RANTES and MIP-1alpha.

The study provides new evidence suggesting that IFN-ß treatment impairs Chemokine-induced T-Cell trafficking by reducing the production of RANTES and MIP-1alpha and the expression of their receptors CCR5.


ImmunoModulatory Effects Of Interferon-ß-1a In MS

Liu Z, Pelfrey CM, Cotleur A, Lee J, Rudick RA
J NeuroImmunol 2001 Jan 1;112(1-2):153-162
Cleveland Clinic Foundation, Dept of NeuroSciences, 44195, Cleveland, OH, USA
PMID# 11108944

Several studies have established a role for Interferon-beta (IFN-ß) as a treatment for Relapsing/Remitting Multiple Sclerosis (MS). IFN-ß has been reported to decrease the relapse rate, relapse severity, progression of disability and development of new Brain lesions.

Its mechanisms of action, however, remain unclear. We hypothesize that ImmunoModulatory effects of IFN-ß may underlie its clinical efficacy.

We used IntraCellular Cytokine flow cytometry to analyze the effects of IFN-ß-1a on expression of the anti-inflammatory Cytokine, IL-10, and its effects on major co-stimulatory molecules in MS patients.

We found that Peripheral Blood MonoNuclear Cells (PBMC) produced more IL-10 following in vitro or in vivo treatment with IFN-ß-1a.

The primary cellular sources of IL-10 were Monocytes and CD4+ T-Lymphocytes.

IL-10 production in response to IFN-ß-1a was increased in unseparated PBMC compared to purified Lymphocyte cultures, indicating that interaction between Monocytes and Lymphocytes may influence IL-10 production in response to IFN-ß-1a.

Using flow cytometry, we monitored the ex vivo expression of two major co-stimulatory pairs-B7/CD28 and CD40/CD40L-before and after intramuscular IFN-ß-1a treatment of MS patients.

IFN-ß-1a lowered the expression of B7.1 on circulating B-Cells and increased B7.2 expression on Monocytes.

CD40 expression on B-Cells was down-regulated, but CD40 on Monocytes was up-regulated by IFN-ß-1a treatment.

These data suggest that co-stimulatory molecules are modulated by IFN-ß, providing a possible mechanism for its in vivo Immune Regulatory effects.


Cloning And Mutation Analysis Of The Human IL-18 Promoter: A Possible Role Of Polymorphisms In Expression Regulation

Giedraitis V, He B, Huang W, Hillert J
J NeuroImmunol 2001 Jan 1;112(1-2):146-152
Huddinge Univ Hospital, Karolinska Institute, Division of Neurology, S-141 86, Huddinge, Sweden
PMID# 11108943

InterLeukin-18 is a proinflammatory Cytokine, which strongly induces IFN-γ production. We have cloned the human IL-18 promoter and screened for possible polymorphisms.

Three single Nucleotide polymorphisms were detected in the promoter and two polymorphisms in the 5'-nontranslated region of the Gene.

Three combinations of these polymorphisms were observed in the Swedish population. All IL-18 promoter Alleles were found to have clear promoter activity when inserted into a luciferase reporter vector.

There were no significant differences in promoter activity between Alleles without stimulation, but after stimulation with PMA/Ionomicin one of the Alleles had clearly lower activity than the other (P<0.01).

Measurement of IL-18 and IFN-γ production in 48 Multiple Sclerosis patients by RT-PCR showed slightly higher expression of IL-18 in individuals homozygous for the most frequent haplotype.

Two IL-18 promoter polymorphisms were analyzed by sequence specific PCR in 208 Multiple Sclerosis patients and 139 healthy controls, however, no significant differences were found.

In summary, our data indicate that common IL-18 promoter polymorphisms influence the expression of IL-18 and potentially also of IFN-γ.


Relationship Between Serum Levels Of IL-10, MRI Activity And Interferon-ß-1a Therapy In Relapsing/Remitting MS

Waubant E, Gee L, Bacchetti P, Sloan R, Cotleur A, Rudick R, Goodkin D
J NeuroImmunol 2001 Jan 1;112(1-2):139-145
UCSF/Mt Zion Multiple Sclerosis Center, 1701 Divisadero Street, 94115, San Francisco, CA, USA
PMID# 11108942

The purposes of this study were to:
  1. Compare monthly Serum IL-10 in patients with Relapsing/Remitting (RR) Multiple Sclerosis (MS) and healthy controls,

  2. Determine the relationship between IL-10 and MRI activity and

  3. Determine the effect of Interferon-beta-1a (IFN-ß-1a) treatment on IL-10 levels.

Median Serum IL-10 levels were lower in untreated RRMS (185.5 pg/ml) compared to controls (438.5 pg/ml) (P=0.19).

Serum levels of IL-10 did not appear to predict the appearance of new Gadolinium-enhancing (Gd+) lesions concurrently or 1 month thereafter.

However, IL-10 levels were more likely to be elevated the month during which Gd+ lesions resolved (OR=3.14, P=0.01).

Median IL-10 levels were lower during IFN-ß-1a treatment (P=0.01).

These observations suggest a relationship between Serum IL-10 levels and resolution of abnormal vascular permeability in new lesions.


Polyclonal ImmunoGlobulins (IVIg) Modulate Nitric Oxide Production And Microglial Functions In Vitro Via Fc Receptors

Stangel M, Compston A
J NeuroImmunol 2001 Jan 1;112(1-2):63-71
Universitatsklinikum Benjamin Franklin, Dept of Neurology, Hindenburgdamm 30, 12200, Berlin, Germany
PMID# 11108934

Controlled trials in Multiple Sclerosis (MS) and case reports in Acute DeMyelinating EncephaloMyelitis (ADEM) have shown that IntraVenous ImmunoGlobulins (IVIg) are of therapeutic benefit in Central Nervous System (CNS) Inflammatory Diseases.

Studies in Experimental AutoImmune EncephaloMyelitis (EAE) have suggested these effects are mediated by modulation of the Cytokine Network and T-Cell responses.

However, there are no data on the influence of IVIg on the local Immune Reaction in the CNS, the site of inflammation in EAE.

We have therefore studied the effect of IVIg on cultured rat Microglia, the main Immune Cell in the CNS.

IVIg increased Nitric Oxide (NO) production in a dose-dependent manner in Microglia stimulated with IFN-γ.

The increase was only marginal in LPS-treated cells, and no effect was seen in untreated Microglia or after stimulation with TNF-alpha or PMA.

This enhancement of NO production depended on the Fc portion of IVIg and could be abrogated by the pharmacological inhibition of Syk and phosphatidylinositol 3-kinase, two enzymes involved in the signalling cascade of Fc receptors.

TNF-alpha secretion was dose-dependently stimulated by IVIg in both untreated Microglia and after stimulation with LPS or IFN-γ.

Again, this effect was mediated through the Fc portion. Finally, we showed that Fc receptor-mediated Phagocytosis was inhibited by IVIg, presumably by blockade of the Fc receptor.

These different effects may protect Oligodendrocytes from AntiBody mediated Phagocytosis and on the other hand could terminate the Immune Reaction by induction of Apoptosis in infiltrating T-Cells via NO and TNF-alpha.

We propose that IVIg, in addition to known effects on the Peripheral Immune System, may also modulate the local Immune Reaction in CNS Inflammatory Disease.


Induction Of Nitric Oxide Synthase And Activation Of NF-kappaB By InterLeukin-12 p40 In Microglial Cells

Pahan K, Sheikh FG, Liu X, Hilger S, McKinney M, Petro TM
J Biol Chem 2000 Dec 7
Univ of Nebraska Medical Center, Oral Biology, Lincoln, NE 68583-0740
PMID# 11110796

InterLeukin-12 (IL-12) is composed of two different subunits - p40 and p35. Expression of p40 mRNA.

But not that of p35 mRNA in excessive amount in the Central Nervous System of patients with Multiple Sclerosis (MS) suggests that IL-12 p40 may have a role in the PathoGenesis of the disease.

However, the mode of action of p40 is completely unknown. The present study was undertaken to explore the role of p40 in the induction of NO production and the expression of iNOS in Microglia.

Both IL-12 and p402, the p40 homodimer, dose-dependently induced the production of NO in BV-2 Microglial Cells. This induction of NO production was accompanied by an induction of iNOS protein and mRNA.

Induction of NO production by the expression of mouse p40 cDNA but not that of the mouse p35 cDNA suggests that the p40 but not the p35 subunit of IL-12 is involved in the expression of iNOS.

In addition to BV-2 Glial Cells, p402 also induced the production of NO in mouse primary Microglia and Peritoneal Macrophages.

However, both IL-12 and p402 were unable to induce the production of NO in mouse primary Astrocytes. Since activation of NF-kB is important for the expression of iNOS.

We investigated the effect of p402 on the activation of NF-kB.

Induction of the DNA-binding as well as the transcriptional activity of NF-kB by p402 and inhibition of p402-induced expression of iNOS by SN50, a cell-permeable Peptide carrying the nuclear localization sequence of p50 NF-kB.

But not by SN50M, a nonfunctional peptide mutant, suggests that p402 induces the expression of iNOS through the activation of NF-kB.

This study delineates a novel role of IL-12 p40 in inducing the expression of iNOS in Microglial Cells which may participate in the PathoGenesis of NeuroInflammatory Diseases.


Myelin Oligodendrocyte GlycoProtein-DNA Vaccination Induces AntiBody-Mediated AutoAggression In Experimental AutoImmune EncephaloMyelitis

Bourquin C, Iglesias A, Berger T, Wekerle H, Linington C
Eur J Immunol 2000 Dec;30(12):3663-3671
Max Planck Institute for NeuroBiology, Dept of NeuroImmunology, Martinsried, Germany
PMID# 11169409

One strategy to reestablish self tolerance in AutoImmune Diseases is based on the use of DNA vaccination to induce ectopic expression of the target AutoAntigen.

We assessed the potential of vaccination with a DNA construct encoding the Myelin Oligodendrocyte Glycoprotein (MOG), an important candidate AutoAntigen in Multiple Sclerosis, to induce Tolerance and protect against Experimental AutoImmune EncephaloMyelitis (EAE).

Unexpectedly, mice vaccinated with MOG-DNA developed an exacerbated form of EAE when challenged with either MOG or an unrelated EncepHalitogen, Myelin Proteolipid Protein.

We demonstrate that this is due to the inability of DNA vaccination to tolerize the MOG-specific T-Cell response.

And to the concomitant induction of a cytopathic MOG-specific AutoAntiBody response, which is pathogenic, enhancing DeMyelination, inflammation and disease severity.

Our data suggest that tolerogenic strategies for AutoImmune Diseases based on DNA vaccination should be approached with caution, as the outcome is unpredictable.


T-Cell Reactivity To Multiple Myelin Antigens In Multiple Sclerosis And Controls

Hellings N, Baree M, Verhoeven C, D'hooghe MB, Medaer R, Bernard CC, Raus J, Stinissen P
J NeuroSci Res 2001 Feb 1;63(3):290-302
Biomedisch Onderzoeksintituut DWI, Limburgs Universitair Centrum, Diepenbeek, Belgium
PMID# 11170179

Myelin proteins, including Myelin Basic Protein (MBP), ProteoLipid Protein (PLP) and Myelin Oligodendrocyte glycoprotein (MOG) are candidate AutoAntigens in MS.

It is not clear whether MS patients show a predominant reactivity to one or several Myelin Antigens.

We evaluated the IFN-γ production induced by MBP and MOG and selected MBP-, MOG- and PLP-Peptides in MS patients and healthy controls using the IFN-γ ELISPOT assay.

Most MS patients and healthy controls showed a heterogeneous Anti-Myelin T-Cell reactivity.

Interestingly in MS patients a positive correlation was found between the anti-MOG and anti-MBP T-Cell responses. No Myelin Peptide was preferentially recognized among the Peptides tested (MBP 84-102, 143-168, MOG 1-22, 34-56, 64-86, 74-96, PLP 41-58, 184-199, 190-209).

In addition the frequency of IL2R(+) MBP reactive T-Cells was significantly increased in blood of MS patients as compared with healthy subjects, indicating that MBP reactive T-Cells exist in an in vivo activated state in MS patients.

Most of the Anti-MBP T-Cells were of the Th1-type because reactivity was observed in IFN-γ but not in IL-4 ELISPOT-assays.

Using Th1 (IL-12) and Th2 (IL-4) promoting conditions we observed that the Cytokine secretion pattern of Anti-MBP T-Cells still is susceptible to alteration.

Our data further indicate that precursor frequency analysis of Myelin reactive T-Cells by proliferation-based assays may underestimate the true frequency of Myelin specific T-Cells significantly.

Copyright 2001 Wiley-Liss, Inc.

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