Approaches that target costimulatory receptors are independent of T-Cell receptor specificity and may be useful for T-Cell-mediated diseases in which the Antigens involved are not well defined.

However, the proper costimulatory pathways need to be targeted. For example, therapies for human T-Cell-mediated diseases need to be effective against previously activated Memory Cells.

In this review, we use AutoImmune DeMyelination as a paradigm for established Immune-mediated PathoGenesis.

Studies with the human disease Multiple Sclerosis and the rodent model Experimental AutoImmune EncephaloMyelitis have suggested that the effectiveness of CD28 blockade.

As a therapeutic strategy for established AutoImmune DeMyelination, may be limited.

ICOS, a receptor that appears to be involved in the costimulation of previously activated T-Cells, may be an attractive alternative.

Copyright 2001 Academic Press.

This paper presents a fully automated algorithm for segmentation of Multiple Sclerosis (MS) lesions from MultiSpectral Magnetic Resonance (MR) images.

The method performs intensity-based tissue classification using a stochastic model for normal Brain images and simultaneously detects MS lesions as outliers that are not well explained by the model.

It corrects for MR field inhomogeneities, estimates tissue-specific intensity models from the data itself, and incorporates contextual information in the classification using a Markov random field.

The results of the automated method are compared with lesion delineations by human experts, showing a high total lesion load correlation.

When the degree of spatial correspondence between segmentations is taken into account, considerable disagreement is found.

Both between expert segmentations, and between expert and automatic measurements.

The development of techniques for the culture of Lymphoid Cells and the isolation of Viruses that infect these cells led to the discovery of human HerpesVirus (HHV) 6 in 1986.

At the time, HHV-6 was the first new human HerpesVirus to be discovered in roughly a quarter of a century.

And its isolation marked the beginning of an era of discovery in HerpesVirology, with the identification of HHV-7 and HHV-8 (Kaposi's Sarcoma-associated HerpesVirus) during the following decade.

Like most Human HerpesViruses, HHV-6 is ubiquitous and capable of establishing a lifelong, latent infection of its host.

HHV-6 is particularly efficient at infecting infants and young children, and primary infection with the Virus is associated with Roseola Infantum (Exanthem Subitum) and, most commonly, an undifferentiated febrile illness.

Viral reactivation in the ImmunoCompromized host has been linked to a variety of diseases, including Encephalitis, and HHV-6 has been tentatively associated with Multiple Sclerosis.

This article discusses the major properties of HHV-6, its association with human disease, and the PathoBiological significance of Viral reactivation.

The BeAn strain of Theiler's Murine EncephaloMyelitis Virus (TMEV) persists in the CNS and produces a chronic inflammatory DeMyelinating Disease that is an animal model for human Multiple Sclerosis (MS).

The mechanisms leading to TMEV-induced DeMyelination are still under study but most likely involve both Immune-mediated and Virus induced damage to cells in the CNS.

Both depending on Viral persistence. It is therefore important to identify the cells in which continued Virus production is permitted.

In this study, we looked at Virus infection in primary Astrocytes, Microglia and Oligodendrocytes, derived from Brains of neonatal susceptible SJL/J mice.

As evidenced by Western blots and ImmunoCytoChemistry, we were able to detect Viral Antigens in all these Brain-derived cells.

In addition, we extended the study to Spinal Cord tissues from mice suffering TMEV-induced disease.

ImmunoHistoChemistry staining with anti-TMEV Sera and Antibodies to specific cell markers detected Viral Antigens in all these cells.

We then asked the question whether Viral Antigen present in these cells, particularly in Microglia/Macrophages, represented true Viral replication or not.

By using different techniques, including ImmunoPrecipitation experiments and the very sensitive method of negative RNA detection through RNase protection assay, we show that both Astrocytes and Oligodendroglia permit de novo Viral replication.

And Viral protein synthesis but with only minimal cytopathic effects. Of these two cell types, Astrocytes carry the brunt of Viral replication.

In Microglia, on the other hand, Viral replication is restricted since only minimal amounts of negative RNA copies can be demonstrated, while there are clear signs that some of these cells undergo Apoptosis.

These findings show that the main cell for Viral replication is the Astrocyte, rather than the Microglia/Macrophage.

Most of the Viral Antigen present in Macrophages, therefore, is probably the result of Phagocytosis, rather than actual Viral replication.

In view of the demonstrated presence of Viral replication in Astrocytes and of great amounts of Viral Antigens in Microglia/Macrophages.

It is possible that both types of cells act as Antigen Presenting Cells during this ImmunoPathological Disease.

In the present study, we have investigated the association of specific polymorphisms of the InterLeukin-1ß (IL-1ß) and IL-1 receptor antagonist (ra) Gene.

With both the susceptibility to and the clinical characteristics of Multiple Sclerosis (MS) in Japanese patients.

We collected and analyzed DNA from 98 MS patients and 104 healthy controls for distribution of IL-1ß or IL-1ra polymorphisms.

Our results show no significant differences in the distribution of the polymorphisms between MS patients and controls.

Furthermore, no association was observed between IL-1ß or IL-1ra polymorphisms and clinical characteristics, such as age at disease onset, clinical course and severity.

Together, our findings suggest that IL-1ß or IL-1ra Gene polymorphisms may not be relevant in the susceptibility to MS or the clinical characteristics of Japanese patients with MS.

We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of Stem Cell collection including methods used, cell yields, effects on disease activity, and complications in patients with AutoImmune Diseases.

Twenty-one unprimed Bone Marrow harvests and 174 peripheral blood Stem Cell mobilizations were performed on 187 patients.

Disease indications were Multiple Sclerosis (76 patients), Rheumatoid Arthritis (37 patients), Scleroderma (26 patients), Systemic Lupus Erythematosus (19 patients), Juvenile Chronic Arthritis (13 patients), Idiopathic AutoImmune Thrombocytopenia (8 patients), Behcet's Disease (3 patients), Undifferentiated Vasculitis (3 patients), Polychondritis (1 patient) and Polymyositis (1 patient).

Bone marrow harvests were used in the Peoples Republic of China and preferred worldwide for children. PBSC mobilization was the preferred technique for adult stem cell collection in America, Australia, and Europe.

Methods of PBSC mobilization included G-CSF (5, 10, or 16 &mgr;g/kg/day) or Cyclophosphamide (2 or 4 g/m(2)) with either G-CSF (5 or 10 &mgr;g/kg/day) or GM-CSF (5 &mgr;g/kg/day).

Bone marrow harvests were without complications and did not affect disease activity.

A combination of Cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone (P < 0.001). g-csf alone was more likely to cause disease exacerbation than the combination of Cyclophosphamide and g-csf (P = 0.003).

Three patients died as a result of Cyclophosphamide-based stem cell collection (2.6% of patients mobilized with Cyclophosphamide).

When corrected for patient weight and apheresis volume, progenitor cell yields tended to vary by underlying disease, prior medication history and mobilization regimen.

Trends in the approaches to, and results of, progenitor cell mobilization are suggested by this survey. While Cytokine-based mobilization appears less toxic, it is more likely to result in disease reactivation.

Optimization with regard to cell yields and safety are likely to be disease-specific and prospective disease-specific studies of mobilization procedures appear warranted.

Myelin Oligodendrocyte Glycoprotein (MOG) has attracted considerable attention due to its possible role in Multiple Sclerosis (MS).

Previous studies have shown that MOG-reactive T-Cells are more commonly detected in MS patients than controls.

In this report, we studied human MOG-reactive T-Cell clones generated from healthy individuals as well as MS patients.

Our results indicate that ImmunoAffinity-purified MOG, which was routinely used in prior studies, is contaminated by Anti-MOG Antibody (mouse IgG), despite the inability to detect IgG by Western blotting.

Here, we used continuous SDS-PAGE, which enabled us to isolate highly purified MOG devoid of contaminating mouse IgG.

The purposes of this study were to investigate the effect of movement repetitions on resistive torque during passive IsoKinetic Dynamometry of the Knee.

And to determine the role of ElectroMyographic activity in the stretched muscles on the torque measurements.

Ten persons with Multiple Sclerosis and HyperTonia of the Knee muscles were compared with 10 healthy age- and gender-matched control subjects.

During series of 10 flexion and extension movements of the Knee at 60, 180 and 300 degrees/s, torque and ElectroMyographic activity in the stretched muscles were registered.

The persons with HyperTonia presented a significantly larger torque reduction (p < 0.05) than the control subjects in all test conditions except for repeated Knee flexion at 300 degrees/s.

ElectroMyographic activity in the stretched muscles was not identified as the only explanatory mechanism for the reduction in HyperTonia during the movement repetitions, suggesting that other factors were also involved.

Objective
To evaluate the expression of Cytokines in both CD4⁺ and CD8⁺ T-Cells derived from peripheral blood of untreated Multiple Sclerosis (MS) patients with either Relapsing/Remitting (RR), Secondary/Progressive (SP) or Primary/Progressive (PP) MS and healthy controls (HC).

Background
MS is an Immune-mediated disease and Cytokines have been hypothesized to contribute significantly to disease progression.

Compared to the Relapse-Onset (RR, SP) form of the disease, PPMS patients have different clinical, Immunological and pathological features.

Surprisingly, the ability of their circulating T-Cells to produce ImmunoRegulatory Cytokines has not been extensively studied so far.

Methods
Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied.

Stimulated peripheral blood derived CD4⁺ and CD8⁺ T-Cells MS patients express significantly more CD4⁺ and CD8⁺ T-Cells were analyzed for IFN-, IL-2, TNF-alpha, IL-4, IL-10 and IL-13 production.

Results
T-Cells producing IFN- compared to HC.

Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4⁺ T-Cells producing IL-2, IL-13 and TNF-alpha and a significant increase in CD8⁺ T-Cells producing IL-4 and IL-10.

Conclusions
The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory Cytokine producing T-Cells.

Compared to the Relapse-Onset form of the disease, confirming the view on PPMS as a distinct disease entity.

Cytokines play an important role in the initiation and maintenance of the inflammatory reaction in Multiple Sclerosis, a Chronic Inflammatory DeMyelinating Disease of the Central Nervous System.

Magnetic Resonance Imaging evidence supports clinical divergence between forms of Multiple Sclerosis with relapses and the Primary/Progressive form without relapses, which shows fewer and smaller inflammatory lesions.

With the aim of understanding better the relative role of pro-inflammatory and/or anti-inflammatory Cytokines in Primary/Progressive Multiple Sclerosis in comparison to Relapsing forms.

We analyzed in 65 patients (24 Primary/Progressive, 20 Relapsing/Remitting and 21 Secondary/Progressive) and 29 healthy controls, the production of Cytokines (IFN-, TNF-, IL-6, IL-10 and IL-12) by peripheral blood MonoNuclear Cells after in vitro stimulation.

We found a similar percentage of Cytokines producing cells between healthy controls and the different clinical forms of Multiple Sclerosis patients.

The ProInflammatory Cytokine Interferon-gamma (IFN-) has been shown to influence the course of Multiple Sclerosis (MS). The IFN- contains a MultiAllelic Dinucleotide repeat in Intron 1.

To investigate whether Alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyzes on 100 sibling pairs from four Nordic countries.

And case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls.

To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases.

We also measured IFN- mRNA levels in unstimulated peripheral blood MonoNuclear Cells from 46 MS patients and 27 controls grouped according to IFN- Intron 1 genotype.

Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results.

Genotype frequencies for Intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the Benign-MS octile differ significantly from those in the Severe-MS octle.

Comparison of IFN- mRNA levels in genotype-conditioned subgroups revealed no significant differences.

Thus, Alleles at the IFNG Intron 1 DiNucleotide repeat appear to affect neither MS susceptibility and severity nor IFN- mRNA expression in vivo.

Correlations between conventional MRI measures of disease activity and clinical disability in Multiple Sclerosis (MS) have been disappointing.

Because ring-enhancing lesions may reflect a more destructive pathology, we tested their potential association with disease severity.

We evaluated active lesions with regard to their enhancement pattern on serial Magnetic Resonance images in a cohort of 28 patients with Relapsing/Remitting MS.

The percentage of ring-enhancing lesions correlated with EDSS, T2 lesion load and duration of disease.

And predicted the occurrence of relapses during the baseline period of observation as well as after 3 years of follow-up in multiple logistic regression analysis.

The findings suggest that the pathological process reflected by ring-enhancing lesions may contribute to more severe clinical disease.