MS Abstracts 4b-2g

Induction of Myelin-specific CD4 T-Cells is a pivotal event in the development of Experimental AutoImmune EncephaloMyelitis (EAE).

Other checkpoints in EAE PathoGenesis have not been clearly defined, although multiple Genetic loci are known to influence EAE development.

We report here that targeted mutation of the Heat-Stable Antigen (HSA) abrogates development of EAE despite a complete lack of effect on induction of AutoImmune T-Cells.

To test whether T-Cell expression of HSA is sufficient, we created TransGenic mice in which HSA is expressed exclusively in the T-Cell lineage. We found that these mice remain resistant to EAE induction.

Adoptive transfer studies demonstrate that both T-Cells and non-T-Cells must express HSA in order for the Pathogenic T-Cells to execute their effector function.

Moreover, HSAIg, a fusion protein consisting of the ExtraCellular domain of the HSA and the Fc portion of ImmunoGlobulin, drastically ameliorates the clinical sign of EAE even when administrated after self-reactive T-Cells had been expanded.

Thus, identification of HSA as a novel checkpoint, even after activation and expansion of self-reactive T-Cells, provides a novel approach for ImmunoTherapy of AutoImmune Neurologic Diseases, such as Multiple Sclerosis.

AutoImmune EncephaloMyelitis can be initiated spontaneously and developed Progressively in TCR TransGenic mice specific for Myelin Basic Protein.

When exposed to non-sterile environment, thus more closely mimicking human Multiple Sclerosis.

By IntraVenous administration of Myelin Basic Protein, we succeeded in reversing the clinical and Pathological signs of Progressive spontaneous disease in these mice.

Flow cytometry showed that the majority of TransGenic T-Cells in Lymph Nodes and Spleen as well as Spinal Cords of treated mice were deleted. Dramatically increased numbers of Apoptotic Cells were found in Peripheral Immune Organs of treated animals.

Proliferative responses of single TransGenic T-Cell to AutoAntigen were significantly decreased in treated mice, indicating that the remaining T-Cells were Anergic. Moreover, production of both Th1 and Th2 Cytokines was suppressed.

This study is the first demonstration of reversal of Progressive, spontaneous AutoImmune Disease of the Central Nervous System, and provides direct evidence that Apoptosis-induced Clonal Deletion, along with Anergy of remaining cells, but not Th2 switch, play a major part in the reversal of this disease by IntraVenous administration of AutoAntigen.

1H Magnetic Resonance Spectroscopy (MRS) provides a unique tool to detect and quantify Brain metabolites.

In Multiple Sclerosis it can be used to investigate Axonal Loss or dysfunction through measurement of N-AcetylAspartate (NAA), a Neuronal marker.

Previous studies in adults have reported variable effects of aging on metabolite concentrations but have predominantly focused on changes in the elderly.

This study has examined a younger adult age group to provide a reference database more applicable to the Multiple Sclerosis population. Single Voxel (volume element) ₁H MRS was carried out in 44 subjects between 22 and 62 years of age.

Sixteen subjects underwent repeat examination after one year. Absolute concentrations of NA (the sum of NAA and N-AcetylAspartate Glutamate), NAA, Creatine/PhosphoCreatine (Cr), Choline containing compounds (Cho) and Myo-Inositol (MI) were measured.

NA, NAA and MI concentrations did not correlate with age but there were significant correlations between age and Cr (r = 0.43, p = 0.004) and Cho (r = 0.38, p = 0. 011) concentrations.

No significant differences in metabolite concentrations were seen over one year. This study provides evidence that age-related changes of metabolite concentrations occur even in a young to middle aged adult population.

This emphasizes the need to perform absolute quantification of metabolite concentrations rather than ratios and the importance of age-matching in ₁H MRS studies of Multiple Sclerosis.

The effect of Baclofen on walking performance was examined in nine Spastic Multiple Sclerosis patients. In addition, nine healthy subjects were tested as controls.

The modulation of the short latency Soleus stretch reflex was closer to normal with Baclofen compared to the recordings without Baclofen.

The modulation index being 74% (range: 60 - 100) with Baclofen and 62% (range: 20 - 100) without Baclofen, P=0.03. In healthy subjects the modulation index was 100% (range: 52 - 100).

In the early swing phase the threshold of the Soleus stretch reflex was significantly higher during Baclofen medication being 139 deg/s (range: 63 - 302) compared with 93 deg/s (range: 37 - 187) without Baclofen, P=0.004.

The relation between the stretch velocity (input) and the amplitude of the stretch reflex (output) in early swing phase was unchanged.

Being 0.27 muVs/deg (range: 0.1 - 1.51) in patients with Baclofen and 0.24 muVs/deg (range: 0.08 - 0.79) without Baclofen, P=0.25.

Baclofen induced no change in input - output properties of the stretch reflex during walking compared with findings in a sitting position at matched EMG activity.

There was a significant correlation between clinical Spasticity score and stretch reflex threshold in the early swing phase (rho=-0.61, P=0.04).

And, between clinical Spasticity score and the slope of the best linear fit in the early swing phase (rho=0.72, P=0.009).

Multiple Sclerosis (2000) 6, 105 - 114

Monthly MRI activity and clinical disability were evaluated in two Relapsing/Remitting Multiple Sclerosis (RRMS) patients for 4 years during a cross-over treatment trial with IFN-ß-1b.

And, for a mean of 21 months after terminating treatment with IFN-ß-1b.

Post-treatment MRI activity was compared to baseline activity in these patients.

Although Contrast Enhancing Lesions (CEL) and the Bulk White Matter lesion load (BWMLL) on T₂-weighted images eventually returned to baseline values.

There was a refractory period of 6 - 10 months after terminating treatment, before baseline MRI activity was restored.

Although the mechanism for a sustained effect of IFN-ß-1b is unclear at this time, these results have important implications for enrollment of such patients into new treatment protocols that rely on contrast enhancing lesion frequency as an outcome measure.

The clinical course of Multiple Sclerosis can be classified as Relapsing from onset (Relapsing/Remitting), or Progressive from onset (Primary/Progressive - PPMS).

These clinical phenotypes have been based on historical and clinical observations.

It has been reported that PPMS patients tend to have quantitatively less MRI activity and disease burden.

We evaluated the sensitivity and diagnostic value of conventional Brain MRI scan in 143 PPMS patients.

Brain MRIs were blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic criteria.

Patients were divided into those with typical, atypical or normal scans. They satisfied Brain MRI criteria in 92% cases.

Findings included: 131 typical, four atypical, and eight normal scans.

All 12 non-typical scans' subjects had Spinal onset; Spinal MRI scans were positive in four of seven cases.

Sex, age of onset, site and number of symptoms involved at onset among those groups were not significantly different.

But, accumulation of disability had a tendency to be slower in these few individuals with normal or atypical head MRI's.

Although there may be quantitative differences in lesion activity/burden, MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that seen in RRMS.

A normal Brain MRI is unusual in PPMS patients.

Tumor Necrosis Factor-alpha (TNF-), a ProInflammatory Cytokine, is believed to play an important role in Multiple Sclerosis (MS) PathoGenesis.

The objective of this study was to determine whether sequence variation in the TNF- Gene is associated with MS.

Bi-allelic PolyMorphisms in the TNF- -238 and -308) and microsatellite TNF- were previously reported.

We investigated these PolyMorphisms in 74 French patients with MS, compared with 75 controls.

No significant differences regarding the TNF- -238 and -308 PolyMorphisms were observed between MS patients and controls.