MS Abstracts 03a-2g1

  1. The ImmunoTherapeutic potential of Melatonin
    Expert Opin Investig Drugs 2001 Mar;10(3):467-76

  2. CerebroSpinal fluid cytologic findings in Multiple Sclerosis. A comparison between patient subgroups
    Acta Cytol 2001 Jan-Feb;45(1):51-9

  3. Interferon-beta induces the development of type 2 Dendritic cells
    Cytokine 2001 Mar;13(5):264-271

  4. Several options for AntiViral treatment trials in Multiple Sclerosis - but which targets should be selected?
    Expert Opin Pharmacother 2000 Sep;1(6):1087-90

  5. Link between ExcitoToxic Oligodendroglial death and DeMyelinating diseases
    Trends NeuroSci 2001 Apr 1;24(4):224-230

  6. Two subsets of Dendritic Cells are present in human CerebroSpinal Fluid
    Brain 2001 Mar;124(Pt 3):480-492

  7. Matrix MetalloProteinases and tissue inhibitors of MetalloProteinases in CerebroSpinal Fluid differ in Multiple Sclerosis and Devic's NeuroMyelitis Optica
    Brain 2001 Mar;124(Pt 3):493-498

  8. Glatiramer Acetate blocks InterLeukin-1-dependent nuclear factor-kappaB activation and RANTES expression in human U-251 MG Astroglial cells
    Brain Res Mol Brain Res 2001 Feb 19;87(1):48-60

  9. Induction of sTNF-R1 and sTNF-R2 by Interferon beta-1b in correlation with clinical and MRI activity
    Acta Neurol Scand 2001 Feb;103(2):105-13


ImmunoTherapeutic Potential Of Melatonin

Maestroni GJ
Expert Opin Investig Drugs 2001 Mar;10(3):467-76
Center for Experimental Pathology, Istituto Cantonale di Patologia, PO Box, 6601 Locarno, Switzerland
PMID# 11227046; UI# 21128175

The interaction between the Brain and the Immune System is essential for the Adaptive Response of an organism against environmental challenges.

In this context, the Pineal NeuroHormone Melatonin (MEL) plays an important role. Helper T-Cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors.

Activation of MEL receptors enhances the release of T-Helper cell Type 1 (Th1) Cytokines, such as Interferon-gamma (IFN-gamma) and IL-2, as well as of novel Opioid Cytokines.

MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human Monocytes.

These mediators may counteract stress-induced ImmunoDepression and other secondary ImmunoDeficiences and protect mice against lethal Viral Encephalitis, Bacterial Diseases and Septic Shock.

Therefore, MEL has interesting ImmunoTherapeutic potential in both Viral and Bacterial infections.

MEL may also influence Haemopoiesis either by stimulating Haemopoietic Cytokines, including Opioids, or by directly affecting specific progenitor cells such as pre B-Cells, Monocytes and NK Cells.

MEL may thus be used to stimulate the Immune Response during Viral and Bacterial infections as well as to strengthen the Immune reactivity as a prophylactic procedure.

In both mice and Cancer patients, the Haemopoietic effect of MEL may diminish the toxicity associated with common ChemoTherapeutic protocols.

Through its pro-inflammatory action, MEL may play an adverse role in AutoImmune Diseases.

Rheumatoid Arthritis patients have increased nocturnal Plasma levels of MEL and their synovial Macrophages respond to MEL with an increased production of IL-12 and Nitric Oxide (NO).

In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect.

In other diseases such as Multiple Sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action.

It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the Immune System homeostasis.

Furthermore, MEL being the Endocrine messenger of darkness, its endogenous synthesis depends on the PhotoPeriod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent.

No information is available concerning this point. Therefore, studies are needed to investigate whether the ImmunoTherapeutic effect of MEL changes with the alternating seasons.


CerebroSpinal Fluid Cytologic Findings In Multiple Sclerosis. A Comparison Between Patient Subgroups

Zeman D, Adam P, Kalistova H, Sobek O, Andel J, Andel M
Acta Cytol 2001 Jan-Feb;45(1):51-9
Charles University, General Teaching Hospital, 1st Medical Faculty, and Faculty of Mathematics and Physics, Depts of Neurology and Clinical BioChemistry, Depts of Probability and Mathematical Statistics, Prague, Czech Republic
PMID# 11213505; UI# 21082243

To compare cytologic findings in CerebroSpinal Fluid (CSF) in various subgroups of Multiple Sclerosis (MS) patients.

Study Design
CSF from 77 patients with clinically definitive or probable MS was examined by means of qualitative cytology.

After the cell count was determined in a Fuchs-Rosenthal chamber, slides were prepared by the CytoSedimentation method and stained with May-Grunwald-Giemsa stain and oil red O and, whenever possible, with Papanicolaou stain and Toluidine blue.

In addition to the differential cell count, the Lymphocyte/Monocyte ratio, percentage of activated forms in the Lymphocytic and Monocytic series, presence and percentage of LymphoPlasmacytes and mature Plasma Cells, presence of Lipophages, Lymphophages and presence of Mitotic figures were evaluated.

The following statistically significant differences were found between the various MS subgroups:

  1. Higher prevalence of Mitotic figures in the Primary/Progressive MS subgroup

  2. Higher prevalence of foam cells and Lymphophages and lower prevalence of CSF Pleocytosis in more severely disabled patients

  3. Lower cell count, lower prevalence of CSF pleocytosis, lower Lymphocyte/Monocyte ratio and lower prevalence of LymphoPlasmacytes in treated patients

  4. Higher prevalence of mature Plasma Cells and Lipophages in MS patients with disease of longer duration

The differences observed in the various MS subgroups may reflect certain aspects of MS PathoGenesis. Qualitative CSF cytology may therefore be useful for both Clinicians and NeuroImmunologists.

Qualitative cytology of CSF is an important diagnostic method that should never be omitted from an examination of CSF from patients with MS.


Interferon-beta Induces The Development Of Type 2 Dendritic Cells

Huang YM, Hussien Y, Yarilin D, Xiao BG, Liu YJ, Link H
Cytokine 2001 Mar;13(5):264-271
Huddinge Univ Hospital, Karolinska Institute, NeuroImmunology Unit, Division of Neurology, Stockholm, Sweden
PMID# 11243704

Suppression of InterLeukin 12 (IL-12) production by Dendritic Cells (DCs) has been hypothesized to be a principal mechanism underlying the biological action of Interferon-beta (IFN-ß).

Used for treatment of Multiple Sclerosis (MS), a chronic inflammatory disease of the Central Nervous System with possible AutoImmune origin. How IFN-ß interacts with DCs to inhibit IL-12 production remains unclear.

In this study, we found that DCs derived from human blood Monocytes, upon culture in the presence of IFN-ß with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and IL-4, differentiated into a population expressing CD14-CD1a-HLA-DR+.

This population expressed CD123 (IL-3Ralpha). IFN-ß dose-dependently increased IL-3Ralpha+DCs and decreased CD1a+DCs.

After 7 days' culture with IFN-ß at a concentration of 10 000 U/ml, more than 40% of DCs expressed IL-3Ralpha.

IFN-ß, together with GM-CSF and IL-4, also induced maturation of IL-3Ralpha-expressing cells, as reflected by upregulation of HLA-DR and of the CoStimulatory molecules CD40, CD80 and CD86.

In contrast to control DCs, IFN-ß-treated DCs produced predominantly IL-10 but only low levels of IL-12p40.

Correspondingly, IFN-ß-treated DCs strongly suppressed IFN-gamma production but enhanced IL-10 production by allogeneic blood MonoNuclear Cells.

Our data suggest that IFN-ß in vitro can induce the development of DC2, which provide a permissive environment for Th2 differentiation. This finding represents a novel mechanism for action of IFN-ß in MS.

Copyright 2001 Academic Press.


Several Options For AntiViral Treatment Trials In Multiple Sclerosis - But Which Targets Should Be Selected?

Bergstrom T
Expert Opin Pharmacother 2000 Sep;1(6):1087-90
Goteborg University, Dept of Virology, S-413 46 Goteborg, Sweden
PMID# 11249480; UI# 21144860

Involvement of viruses in the PathoGenesis of Multiple Sclerosis (MS) is a long-lived hypothesis, which is has not yet been proven nor refuted.

This is partly due to difficulties in the evaluation of diagnostic findings on persistent infections by common Viruses such as HerpesViruses and endogenous RetroViruses.

Progress in AntiViral treatment of Central Nervous System (CNS) HerpesVirus infections has stimulated controlled trials of long-term therapy with Acyclovir and Valacyclovir in MS, but conclusive results are not yet available.

Other treatment possibilities might include AntiRetroViral therapy, as well as attempts to counteract the effects of Viruses in triggering attacks of MS following Upper Respiratory Tract infections.

Before such trials are initiated, however, further diagnostic evidence of the involvement of target Viruses seems warranted.


Link Between ExcitoToxic Oligodendroglial Death And DeMyelinating Diseases

Matute C, Alberdi E, Domercq M, Perez-Cerda F, Perez-Samartin A, Sanchez-Gomez MV
Trends NeuroSci 2001 Apr 1;24(4):224-230
Universidad del Pais Vasco, Departamento de Neurociencias, 48940, Leioa, Spain
PMID# 11250007

Oligodendrocytes, the Myelinating cells of CNS Axons, are highly vulnerable to ExcitoToxic signals mediated by Glutamate receptors of the AMPA and Kainate classes.

Receptors in these cells are commonly activated by Glutamate that is released from Axons and Glial Cells.

In addition, Oligodendrocytes contribute to the control of ExtraCellular Glutamate levels by means of their own transporters.

However, acute and chronic alterations in Glutamate homeostasis can result in overactivation of AMPA and Kainate receptors and subsequent ExcitoToxic Oligodendroglial death.

Furthermore, DeMyelinating lesions caused by ExcitoToxins can be similar to those observed in Multiple Sclerosis.

This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the Neurological score of animals with Experimental AutoImmune EncephaloMyelitis, indicates that Oligodendrocyte ExcitoToxicity could be involved in the PathoGenesis of DeMyelinating Disorders.


Two Subsets Of Dendritic Cells Are Present In Human CerebroSpinal Fluid

Pashenkov M, Huang YM, Kostulas V V, Haglund M, Soderstrom M, Link H
Brain 2001 Mar;124(Pt 3):480-492
Karolinska Institutet, Huddinge Univ Hospital, Divisions of Neurology, Infectious Diseases and Ophthalmology, Stockholm, Sweden
PMID# 11222448

Little is known about the presence of Dendritic Cells in the human CNS.

To investigate the occurrence of Dendritic Cells in the CSF, paired blood/CSF samples from patients with Multiple Sclerosis, Acute Optic Neuritis, Lyme NeuroBorreliosis, other inflammatory Neurological Diseases and non-inflammatory Neurological Diseases were examined using flow cytometry.

Almost all CSF samples contained Myeloid (lin- CD11c+ HLA-DR++ CD123(dim)) and plasmacytoid (lin-CD11c- HLA-DR+ CD123(high)) Dendritic Cells. In Non-Inflammatory Neurological Diseases, Dendritic Cells of either subset only constituted up to 1% of CSF MonoNuclear Cells.

Myeloid CSF Dendritic Cells were elevated in Optic Neuritis, NeuroBorreliosis and other inflammatory Neurological Disorders, while Plasmacytoid Dendritic Cells were elevated in all NeuroInflammatory conditions studied, with especially high numbers in NeuroBorreliosis.

Numbers of CSF Dendritic Cells correlated with the common parameters of CNS inflammation.

The Myeloid Dendritic Cells in CSF expressed higher levels of HLA-DR, CD86, CD80 and CD40 than those in blood, whereas expression of these molecules by Plasmacytoid Dendritic Cells was equal in blood and CSF.

Both CSF and blood Dendritic Cells expressed the Chemokine receptor CCR5. This is the first demonstration that Dendritic Cells are present in human CSF and that Plasmacytoid Dendritic Cells are present in a Non-Lymphoid compartment.

Myeloid and Plasmacytoid Dendritic Cells in CSF may contribute to orchestration of the local Immune Responses.


Matrix MetalloProteinases And Tissue Inhibitors Of MetalloProteinases In CerebroSpinal Fluid Differ in Multiple Sclerosis And Devic's NeuroMyelitis Optica

Mandler RN, Dencoff JD, Midani F, Ford CC, Ahmed W, Rosenberg GA
Brain 2001 Mar;124(Pt 3):493-498
Univ of New Mexico Health Sciences Center, Depts of Neurology, NeuroScience and Cell Biology and Physiology, Albuquerque, New Mexico, USA
PMID# 11222449

Matrix MetalloProteinases (MMPs) are increased in the CSF of patients with Multiple Sclerosis. Devic's Neuromyelitis Optica (DNO) is a DeMyelinating syndrome that involves the Optic Nerve and Cervical Cord but differs pathologically from Multiple Sclerosis.

Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in Multiple Sclerosis would be absent in patients with DNO.

CSF was collected from 23 patients with Relapsing/Remitting or Secondary/Progressive Multiple Sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers.

Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of Multiple Sclerosis patients but not in that of DNO patients.

Zymography, reverse zymography and ELISA (Enzyme-Linked ImmunoSorbent Assay) were used to measure Gelatinase A (MMP-2), Gelatinase B (MMP-9) and Tissue Inhibitors of MetalloProteinases (TIMPs).

Zymograms showed that Multiple Sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups.

We conclude that Multiple Sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.


Glatiramer Acetate Blocks InterLeukin-1-Dependent Nuclear Factor-kappaB Activation And RANTES Expression In Human U-251 MG Astroglial Cells

Li QQ, Bever CT
Brain Res Mol Brain Res 2001 Feb 19;87(1):48-60
Univ of Maryland School of Medicine, Depts of Neurology, Pharmacology, and Experimental Therapeutics, 21201, Baltimore, MD, USA
PMID# 11223159

RANTES is a basic 8-kDa polypeptide of the C-C Chemokine subfamily with strong ChemoAttractant activity for T-Lymphocytes and Monocytes/Macrophages that are implicated in the PathoGenesis of Multiple Sclerosis (MS) lesions.

Glatiramer Acetate is a drug recently approved for the treatment of MS. We therefore investigated the effect of Glatiramer Acetate on RANTES expression in Glial Cells in vitro.

Treatment of human U-251 MG Astroglial cells with Glatiramer Acetate blocks IL-1ß-induced RANTES Chemokine production in a dose- and time-dependent manner.

Glatiramer Acetate also decreased steady-state levels of RANTES mRNA in these cells, which was attributable to reduced transcription, as assessed by nuclear run-on assays.

In addition, we showed that NF-kappaB may be the transcriptional activator responsible for the IL-1ß-mediated RANTES Gene expression in this system.

Our data indicated that the IL-1ß-induced increase in RANTES was associated with an increase in in vitro nuclear extract binding activity specific for the NF-kappaB site in the promoter region of the RANTES gene.

The increases in RANTES mRNA and protein expression were suppressed by the NF-kappaB inhibitors GlioToxin, IsoHelenin, and Pyrrolidine Dithiocarbamate (PDTC).

Furthermore, we demonstrated that the increase in NF-kappaB DNA-binding activity was prevented by pretreatment with Glatiramer Acetate or the NF-kappaB inhibitors.

Our results suggest that Glatiramer Acetate may inhibit IL-1ß-stimulated RANTES expression in human Glial Cells by blocking NF-kappaB activation, thus identifying part of the molecular basis for its anti-inflammatory and ImmunoSuppressive effects in DeMyelinating Diseases.


Induction Of sTNF-R1 And sTNF-R2 By Interferon beta-1b In Correlation With Clinical And MRI Activity

Laske C, Oschmann P, Tofighi J, Kuehne SB, Diehl H, Bregenzer T, Kraus J, Bauer R, Chatzimanolis N, Kern A, Traupe H, Kaps M
Acta Neurol Scand 2001 Feb;103(2):105-13
Justus-Liebig Univ, Dept of Neurology, Giessen, Germany
PMID# 11227128; UI# 21118711

To investigate the influence of Interferon-1b (IFN-ß-1b) on the Serum levels of sTNF -R1, sTNF-R2 and TNF-beta in patients with Multiple Sclerosis (MS) in correlation with clinical and MRI activity.

Materials And Methods
Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN-ß-lb every other day (treatment group).

And from 21 patients without any ImmunoModulatory therapy (control group) over a 15-month observation period.

The Cytokine levels were measured by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease of every patient.

In the treatment group we found an obvious increase of sTNF-R1 and sTNF-R2 (P < 0.001) and relatively stable Serum levels of TNF-ß with no statistical significance (P = 0.56).

In the control group, sTNF-R1 showed a significant decrease (P < 0.001) during the same observation period of 15 months.

During the 15-month observation period, the MRI-responders group had significant larger mean AUC (area under the concentration-time curve) values of sTNF-R1 (P = 0.04) and sTNF-R2 (P = 0.01) when compared to the group of MRI nonresponders.

The present data suggest that IFN-ß-1b induces the expression and shedding of TNF-R1 and TNF-R2. The magnitude of an increase of sTNF-Rs may be a marker for the effectiveness of treatment with IFN-ß-1b.

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