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.

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.

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--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.

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

The results support the conclusion that although delta 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.

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.

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.

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.

Objectives
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.

Methods
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.

Results
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.

Conclusion
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.

Objective
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.

Results
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.

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