Multiple Sclerosis (MS) is a Neurological Disease that affects the Central Nervous System (Brain and Spinal Cord) resulting in debilitating Motor and Sensory Dysfunction.

Its mean age of onset is 30 years and, with the exception of trauma, MS remains the most frequent cause of Neurological Disabilities for young adults.

The disease is highly variable in its onset and progression. It may not be easily diagnosed, at least in its earliest stages. Significant disability is a hallmark of MS.

Indeed, up to 50% of patients require walking aids and 10% are wheelchair-bound at 15 years after an initial diagnosis.

Clinical features include deficits in Sensory (Paresthesias and Numbness), Motor (difficulties with fine movements and Gait), Balance, Badder, and Sexual functions.

Although the Etiology for MS is not yet known, it is thought to be related to Microbial, Genetic, and/or Environmental factors.

Pathologically, MS is characterized by Inflammation. An influx of MonoNuclear Cells occurs through a disrupted Blood-Brain Barrier into an Immune-privileged Central Nervous System.

The secretion of a variety of inflammatory Cytokines and Chemokines from Glial Cells leads to loss of Myelin, disruption of Oligodendrocyte integrity, and Axonal loss.

These events, in large measure, affect progressive Neural Atrophy. How Brain inflammatory activities affect TransEndothelial migration of Leukocytes into the Brain and alter the process of Myelination are the focal points for MS research activities.

Interferon gamma (IFN-) stimulates the (pro-inflammatory) Type II Interferon receptor and is known to exacerbate Multiple Sclerosis (MS).

In contrast, IFN- and IFN-ß are Ligands for the (anti-inflammatory) Type I Interferon receptor and are beneficial in some (but not all) patients with MS.

Should IFN-ß elicit a Type-II-like pro-inflammatory response, the beneficial effects might be attenuated. These studies were undertaken to test this possibility with the use of Quinolinic Acid (QUIN) formation as a measure of Type II receptor activation.

In normal human Macrophage cultures, IFN- was the most potent stimulus for QUIN formation.

Generally, IFN-ß and IFN- were less potent. However, an unexpected inter-patient variability was observed.

In some subjects, IFN- was more potent than IFN-ß.

In other subjects, IFN-ß was more potent than IFN-.

The present data demonstrate an inter-subject variability for QUIN production following exposure to the Interferons.

MS patients who demonstrate a pro-inflammatory response to IFN-ß (e.g., increased QUIN) may be less likely to benefit from this therapy.

We assessed the relative sensitivities of standard (SD)- and triple-dose (TD) Gadolinium (Gd)-enhanced Magnetic Resonance Imaging (MRI).

For detecting enhancing lesions in different phases of Multiple Sclerosis (MS) disease activity.

Ten MS patients were studied with monthly Brain MRI scans for a 3-month follow-up (i.e., 4 scans were obtained for each patient with both SD and TD).

A total of 11 relapses were recorded and treated with short-term high-dose Steroid therapy. Enhancing lesion numbers and volumes were significantly higher for TD vs. SD scans (p < 0.0001).

For both Gd doses, the numbers and volumes of lesions were higher during clinical relapses; the differences were statistically significant when comparing the results for scans obtained during and after a relapse.

The gain in sensitivity of TD vs. SD scans for enhancing lesion detection was lower during relapses, whilst it was maximum after relapses, although these differences did not reach statistical significance.

Our data confirm the potential role of TD MRI for monitoring MS activity, since, with its higher sensitivity, it may detect more subtle Blood-Brain Barrier (BBB) damage.

They also suggest that the degree of BBB damage in individual lesions changes during different phases of disease activity.

We have determined that certain Altered Peptide Ligands (APLs) can induce T-Cells specific for the native Peptide Myelin Basic Protein (MBP) p85-99 to secrete Th2-type Cytokines such as IL-4 and IL-5 in the absence of significant Th1-type Cytokines.

However, it is not known whether stimulation with APLs will activate AutoReactive T-Cells or a distinct population of cells.

In the present study, 18 T-Cell clones that reacted with either MBP p85-99 or one of three APLs of the Peptide substituted at TCR contact residues were generated.

T-Cells were tested functionally for their reactivity to the original stimulating Peptide as well as to the MBP APLs.

In addition, the T-Cell receptor (TCR) and ß chains of each of these clones were sequenced.

In a series of T-Cell clones isolated from a Multiple Sclerosis patient, stimulation of T-Cells with the APL 93A.

Which has an alanine for Lysine substitution at the TCR contact residue 93, did not induce substantial proliferation of MBPp85-99-specific T-Cell clones, indicating that a distinct set of T-Cell clones was induced.

However, this was not the case for another set of T-Cell clones from a different individual in which the 93A peptide induced clonal expansion of T-Cells highly reactive with the native MBPp85-99 Antigen.

Thus, the potential beneficial effect of using APLs to induce downregulatory Cytokines appears to depend on the specific T-Cell repertoire of the individual patient.

Copyright 1999 Academic Press.

delta T-Lymphocytes are thought to play a role in the PathoGenesis of Multiple Sclerosis (MS) contributing to DeMyelination and fibrosis in the Central Nervous System.

In this study, we show that, in MS patients with active disease, the percentage of circulating Vdelta2+ delta T-Cells coexpressing NKRP1A is significantly increased.

Compared with healthy donors, Vdelta2+ and Vdelta1+ T-Cells were sorted from MS patients and healthy volunteers and cloned.

At variance with Vdelta1+ clones, all Vdelta2+ clones expressed NKRP1A, which was strongly up-regulated upon culture with IL-12.

This effect was neutralized by specific anti-IL-12 Abs. No up-regulation of NKRP1A by IL-12 was noted on Vdelta1+ clones.

RNase protection assay showed that IL-12R beta2 subunit transcript was significantly less represented in Vdelta1+ than Vdelta2+ clones. This finding may explain the different effect exerted by IL-12 on these clones.

In TransEndothelial migration assays, Vdelta2+ NKRP1A+ clones migrated more effectively than Vdelta1+ clones, and this migratory potential was enhanced following culture with IL-12.

Migration was strongly inhibited by the F(ab')2 of an anti-NKRP1A Ab, suggesting that this lectin is involved in the migration process.

We also show that, in freshly isolated PBMC from MS patients, the migrated population was enriched for Vdelta2+ NKRP1A+ cells.

We conclude that the expression of NKRP1A on Vdelta2+ Cells is associated with increased ability to migrate across the Vascular Endothelium and that this phenomenon may be regulated by IL-12 present in the MicroEnvironment.

Background
The importance of evaluating disability outcome measures is well recognized.

The Functional Independence Measure (FIM) was developed to be a more comprehensive and "sensitive" measure of Disability than the Barthel Index (BI).

Although the FIM is widely used and has been shown to be reliable and valid, there is limited information about its responsiveness, particularly in comparison with the BI.

This study compares the appropriateness and responsiveness of these two disability measures in patients with Multiple Sclerosis and Stroke.

Methods
Patients with Multiple Sclerosis (n=201) and PostStroke (n=82) patients undergoing inpatient NeuroRehabilitation were studied.

Admission and discharge scores were generated for the BI and the three scales of the FIM (total, Motor, and Cognitive).

Appropriateness of the measures to the study samples was determined by examining score distributions, floor and ceiling effects.

Responsiveness was determined using an effect size calculation.

Results
The BI, FIM total, and FIM Motor Scales show good variability and have small floor and ceiling effects in the study samples.

The FIM Cognitive Scale showed a notable ceiling effect in patients with Multiple Sclerosis.

Comparable effect sizes were found for the BI, and two FIM scales (total and Motor) in both patients with Multiple Sclerosis and Stroke patients.

Conclusion
All measures were appropriate to the study sample. The FIM Cognitive Scale, however, has limited usefulness as an outcome measure in progressive Multiple Sclerosis.

The BI, FIM total, and FIM motor scales show similar responsiveness, suggesting that both the FIM total and FIM Motor Scales have no advantage over the BI in evaluating change.