MS Abstracts: 1a-2g

An endogenous factor that is able to reduce the fast transient Sodium current of excitable cells has been reported to exist in the CerebroSpinal Fluid (CSF) of Multiple Sclerosis (MS) patients.

This was confirmed with nine Clinically Definite MS patients in the acute relapse. In order to purify and chemically identify the factor, MicroConcentration and gel filtration High-Performance Liquid Chromatography (HPLC) were applied.

After each purification step the activity-containing fraction was determined using a biological assay. With all CSFs the activity was contained in the fraction corresponding to 600-800 Da molecular weight, indicating that the factor is chemically homogeneous.

The biological activity of the CSF specimens was not correlated to the laboratory CSF data; however, it was correlated to the area under the 210 nm UV light absorption peak in the corresponding ChromatoGram, i.e. the 600-800 Da MW fraction.

As the factor was degradable by Acid Hydrolysis and a CarboxyPeptidase, it is suggested that it might be a small peptide.

The presence of OligoClonal Bands in CerebroSpinal Fluid (CSF) in Multiple Sclerosis (MS) indicates a restricted Heterogeneity of ImmunoGlobulin (Ig). The portion of Myelin Basic Protein encompassing residues 80-96 contains Epitopes frequently recognized by T and B-Cells of MS patients.

To define further this restricted Heterogeneity and to direct further efforts to identify an Antigenic target of CSF OligoClonal Bands, the presence of Idiotope (Id)-bearing AntiBodies sharing an Id with a murine MonoClonal AntiBody to Myelin Basic Protein peptide 80-89 was examined in the CSF of MS patients.

CSF samples from 57 patients with Clinically Definite MS and 45 patients with Other Neurological Diseases were standardized for amount of IgG and analyzed by ImmunoBlotting for detection of Id-bearing AntiBodies.

Id-bearing Ig was detected in the CSF of 79% of MS patients and 16% of Other Neurological Disease patients. Further statistical analysis revealed an 84% specificity, an 86% positive predictive value, and a 76% negative predictive value of the test.

The probability that a positive screening result indicated MS was 81%. Thus, AntiBodies containing a cross-reactive Id are present preferentially in the CSF of patients with MS compared with those with Other Neurological Diseases.

An Immune Network that has limited V region Gene usage likely exists in the CSF and Central Nervous System of patients with MS and may provide evidence about Antigens relevant to the PathoGenesis of MS.

To clarify the Th1/Th2 balance in Spinal Cord inflammation, we used ELISA to measure the total and Allergen-specific IgE in 69 patients with Clinically Definite Multiple Sclerosis (MS).

Including 24 patients with the Optico-Spinal form of MS, 45 with HAM/TSP, 30 HTLV-I carriers without HAM/TSP, 40 patients with acute Myelitis, 43 with NeuroDegenerative Disorders, and 42 healthy subjects.

And flow cytometry to study the IntraCellular IFN--positive (IFN-⁺) versus IL-4-positive cell ratio (IntraCellular IFN-gamma/IL-4 ratio) in Peripheral blood CD4⁺ T-Cells in 40 patients with MS. Including:

• 17 patients with the Optico-Spinal form of MS
• 23 with HAM/TSP
• 22 with Acute Myelitis
• 23 with NeuroDegenerative Disorders
• and 36 healthy subjects

Patients with HAM/TSP showed a significantly higher IntraCellular IFN-^-/IL-4 ratio, lower IL-4⁺/IFN-^- cell percentages, lower total IgE level, and lower frequency of cedar pollen-specific IgE than did the controls.

The patients with Optico-Spinal MS showed a significantly higher IntraCellular IFN-gamma/IL-4 ratio and higher IL-4^-/IFN-⁺ cell percentages than the controls even at remission or in the convalescence phase.

In contrast, in the patients with Acute Myelitis, the total Serum IgE level and the frequency of mite Antigen-specific IgE were significantly elevated in comparison to the controls.

While those having mite Antigen-specific IgE Myelitis showed a significantly lower IFN-/IL-4 ratio in the CD4⁺ T-Cells in comparison to the controls.

These findings suggest that the Th1 cell response is predominant in HAM/TSP and Optico-Spinal MS, whereas the Th2 cell response is predominant in mite Antigen-specific IgE Myelitis.

Human HerpesVirus 6 (HHV-6) is the Etiologic agent of Exanthema Subitum, causes opportunistic infections in ImmunoCompromized patients, and has been implicated in Multiple Sclerosis and in the progression of AIDS.

Here, we show that the two major HHV-6 subgroups (A and B) use human CD46 as a cellular receptor. Downregulation of surface CD46 was documented during the course of HHV-6 infection.

Both acute infection and cell fusion mediated by HHV-6 were specifically inhibited by a Monoclonal AntiBody to CD46; fusion was also blocked by soluble CD46.

Nonhuman cells that were resistant to HHV-6 fusion and entry became susceptible upon expression of recombinant human CD46. The use of a ubiquitous ImmunoRegulatory Receptor opens novel perspectives for understanding the Tropism and Pathogenicity of HHV-6.

When a life-threatening or chronic disease is diagnosed, patients may find that their sense of time, the passage of days, and their view of the future are altered. Most of the time, people live in a sense of linear time, or Kronos.

When illness strikes, they may begin to spend more time in kairos, a sense of soul-satisfying time, such as the feeling one gets when walking on the seashore with a grandchild, working in the garden, or talking with friends over good food and wine.

This article comments on two patients, one who explores kairos through a diary that documents her positive attitude toward coping with Multiple Sclerosis, and one, a young artist with Hodgkin disease, who explores his condition through 96 paintings of his experience of the disease.

Rather than "the devouring tyrant of linear time," life can be seen in a circular fashion, the eternal braid of Hofstadter. Patients begin to see life more in terms of cycles of daily events, routines, and the change of seasons.

Illness brings one "close to the bone" of the soul's needs, with a reappraisal of the journey of life as a continuous line, to life spread out on a landscape that includes the past and the future.

The Immune System is involved in the PathoPhysiology of Multiple Sclerosis (MS) but the initiating Antigen(s) is not yet identified. Since Cytokines control both the intensity and the quality of the Immune Response they may be relevant candidates for the Genetic susceptibility to MS.

To analyze the contribution of type 1 and type 2 Cytokine and Cytokine Receptor Genes in the Genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 Cytokine or Cytokine Receptor Genes using 31 highly polymorphic Genetic markers.

The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate Genes tested was significantly linked to MS on the whole population.

However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the Genetic susceptibility in a subgroup of MS patients.

Chemokines and Matrix MetalloProteinases (MMPs) appear to be crucial in Leukocyte recruitment to the Central Nervous System in Multiple Sclerosis (MS).

CCR5 delta32, a truncated allele of the CC Chemokine Receptor CCR5 Gene encoding a non-functional receptor, did not confer protection from MS.

CCR5 delta32 was, however, associated with a lower risk of recurrent clinical disease activity. High CSF levels of MMP-9 activity were also associated with recurrent disease activity.

These results directly link Intrathecal inflammation to disease activity in patients with MS, suggesting that treatments targeting CCR5 or treatment with MMP inhibitors may attenuate disease activity in MS.

Pathogenic AutoReactive T-Cells can be targeted by T-Cell Vaccination (TCV), a procedure in which patients are immunized with autologous attenuated Pathogenic T-Cells.

We reported previously that TCV with Myelin Basic Protein (MBP) reactive T-Cell clones in Multiple Sclerosis (MS) patients induced T-Cell Immune Responses, resulting in a clonal depletion of MBP reactive T-Cells in all patients.

Five years after TCV, MBP reactive T-Cells were observed in five out of nine MS patients. These clones had a different clonal origin from those isolated before vaccination.

We have studied the Cytokine profile, cytotoxicity and Epitope specificity of these reappearing clones. Our data indicate that the clones express similar effector functions as those isolated before TCV, suggesting that they also could play a Pathogenic role in the disease.

We demonstrated that these clones can be depleted by an additional sequence of immunizations. These findings may be relevant to other T-Cell targeted ImmunoTherapies for MS and other AutoImmune Diseases.

Treatment with MonoClonal anti-IL-12 AntiBody injected on day 0, 7 and 10 after immunization with Myelin Oligodendrocyte Glycoprotein (MOG) peptide 35-55 in NOD mice.

Resulted in significant suppression of the development and the severity of the Chronic Relapsing/Remitting Experimental AutoImmune EncephaloMyelitis (EAE) both clinically and histologically.

The Spleen Cells from anti-IL-12 AntiBody treated mice displayed markedly inhibited MOG35-55 specific proliferation and IFN- production. MOG35-55 specific AntiBody production was enhanced by anti-IL-12 AntiBody treatment.

These results suggest that IL-12 is critically involved in the PathoGenesis of MOG-induced EAE and that AntiBody to IL-12 could be an effective therapeutic agent in the clinical treatment of AutoImmune DeMyelinating diseases such as Multiple Sclerosis (MS).

Dexanabinol (HU-211) is a synthetic Non-Psychotropic Cannabinoid which suppresses TNF- production in the Brain and peripheral blood.

The effects of Dexanabinol in rat Experimental AutoImmune EncephaloMyelitis (EAE) were studied using different doses, modes of administration and time regimes.

Dexanabinol, 5 mg/kg i.v. given once after disease Onset (day 10), significantly reduced maximal EAE score. Increasing the dose or treatment duration resulted in further suppression of EAE.

Drug administration at earlier phases during disease induction was not effective. Histological studies supported the clinical findings demonstrating reduction in the inflammatory response in the brain and spinal cord in animals treated with Dexanabinol.

The results suggest that Dexanabinol may provide an alternative mode of treatment for acute exacerbations of Multiple Sclerosis (MS).

Fifty seven patients (42 males and 15 females) with non-compressive Myelopathy were studied from 1997 to 1999.

Acute Transverse Myelitis (ATM) was the commonest (31) followed by Vit B12 Deficiency Myelopathy (8), Primary/Progressive Multiple Sclerosis (5), Hereditary Spastic Paraplegia (3), Tropical Spastic Paraplegia (2), Subacute Necrotising Myelitis (1), Radiation Myelitis (1), Syphilitic Myelitis (1) and Herpes Zoster Myelitis (1).

4 cases remained unclassified. In the ATM group, mean age was 30.35 years, antecedent event was observed in 41.9% case, 25 cases had symmetrical involvement and most of the cases had severe deficit at Onset.

CSF study carried out in 23 patients of ATM revealed rise in proteins (mean 147.95mg%, range 20-1200 mg/dL) and PleoCytosis (mean 20.78/cumm, range 0-200 mm3). OligoClonal Band (OCB) was present in 28% of cases of ATM.

The most common abnormality detected was a multisegment HyperIntense lesion on T2W images, that occupied the central area on cross section. In 6 patients HyperIntense signal was eccentric in location. MRI was normal in 4 cases of ATM.