MS Abstracts 3c-2g1

Introduction
Global Magnetization Transfer Ration (MTR) Histogram analysis in the Brain offers a method for evaluating pathological change both as a result of lesions and microscopic changes in Normal Appearing Tissues.

Methods
39 controls and 83 MS patients (46 Primary/Progressive, 11 Benign, 10 Relapsing/Remitting, 16 Secondary/Progressive) were studied to explore the relationship of six conventional MTR Histogram parameters with MS clinical subgroups and disability.

Principal Component (PC) analysis, which makes use of all the Histogram data, was also used to examine the relationship between the MTR Histogram and disability.

Results
When Primary/Progressive patients were compared to controls, there were abnormalities of average MTR, and MTR at the 25th, 50th and 75th percentile.

Disabled Relapsing onset patients exhibited abnormalities in the same four parameters. Benign and nondisabled Relapsing onset patients exhibited no significant abnormalities.

Modest correlations were observed between Disability and individual MTR parameters in Relapsing onset but not Primary/Progressive patients.

PC analysis revealed stronger and significant associations with disability in both subgroups. (r=0.40 for Primary/Progressive and r=0.51 for Relapsing onset).

Conclusion
A number of MTR parameters are abnormal in Primary/Progressive MS. MTR abnormalities are seen in disabled patients, whether of Relapsing or Primary/Progressive onset.

The improved correlation with disability obtained by PC analysis suggests a useful role of this method for following clinically relevant pathological changes depicted in the MTR Histogram.

Background And Objectives
The aim of this study was to evaluate the tolerability and effectiveness of a Non-MyeloAblative conditioning regimen followed by autologous Hematopoietic Stem Cell infusion for the treatment of severe AutoImmune Diseases.

Design And Methods
From 1996 patients with severe AutoImmune Disease not responsive to conventional Immunosuppressive treatment were selected.

The patients' blood or marrow cells were harvested after incubation with Vincristine and Methylprednisolone. Two different ImmunoAblative conditioning regimens were employed.

The first used Cyclophosphamide (2500 mg/m2 in one day) and AntiLymphocyte Globulin (ALG) (15 vials/m2 in three days) and the second used Fludarabine (300 mg/m2 in two courses of 5 days) plus ALG (25 vials/m2 in 5 days).

Results
Nineteen patients (14 female, 5 male) with severe AutoImmune Diseases were treated. Nine had a Rheumatologic Disorder (5 Juvenile Chronic Arthritis, 1 Rheumatoid Arthritis, 1 Systemic Vasculitis, 1 Sjogren's Syndrome, 1 Behct's Disease), 4 a Neurologic Disorder (3 Multiple Sclerosis, 1 Myasthenia), 3 a Haematologic Disease (2 Pure Red Cell Aplasia, 1 AutoImmune Thrombocytopenia), 2 had a Gastrointestinal Disease (1 Crohn's Disease, 1 AutoImmune Enteropathy) and 1 had a multiple AutoImmune Disorder.

There was no regimen-related toxicity and no opportunistic infections occurred. Ninety percent of the patients improved and/or had a complete remission after the procedure.

Fifty percent of the subjects went into complete or partial remission after a median follow-up of 15 months (range 3-25) while 50% relapsed after a median follow-up of 11 months, (range 6-16).

The incidence of relapse in the group treated with Fludarabine was lower (30%).

Interpretation And Conclusions
A Non-MyeloAblative conditioning regimen was able to induce persistent remission in some patients with severe AutoImmune diseases.

There was no mortality or morbidity related to the procedure. The extent of remission does, however, remain to be established.

In the animal model for Multiple Sclerosis (MS), Experimental AutoImmune Encephalitis (EAE), Genetic loci correlating with incidence or severity of disease are located both within and outside of the Major Histocompatibility Complex (MHC).

Whereas polymorphisms within MHC Class I and II molecules are likely to be a major determinant of MHC Gene influence in rat EAE, it is still unclear how non-MHC Gene regions influence disease.

Genetic control of inflammation can hypothetically be either general or specific for a particular target tissue.

For the latter, Gene regulation of PathoMechanisms in the CNS could affect reactivity of Microglia or Astrocytes, local Cytokine/Chemokine production, or even Neuronal vulnerability.

We have obtained strong support for this notion by observations of rat strain-dependent variation in the inflammatory response after ventral root avulsion, a model in which mainly non-antigen-specific elements of the Immune System promote inflammation.

A comparison of strains with similar MHC haplotypes on different backgrounds and strains with different MHC haplotypes on the same background, respectively, demonstrates that the inflammatory phenotype is regulated mainly by non-MHC Genes.

Interestingly, different features of the inflammatory response, such as induction of MHC Class II expression, Glial activation, Cytokine expression, and Neuronal vulnerability, varied between rat strains and were largely independent of each other.

The Genetic control of several basic features of inflammation in the CNS is of great relevance not only for MS/EAE, but also for several other Neurological conditions with inflammatory components such as CerebroVascular and NeuroDegenerative Dieases and Trauma.

DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental AutoImmune diseases.

These diseases include Rheumatoid Arthritis models such as Collagen-Induced Arthritis (CIA) and Adjuvant-Induced Arthritis (AIA), Multiple Sclerosis models such as Myelin-Basic-Protein (MBP)-induced Experimental AutoImmune EncephaloMyelitis (MBP-EAE).

And AutoImmune Uveitis models such as Retinal S antigen (SAG) and Interphotoreceptor-Retinoid-Binding-Protein (IRBP)-induced Experimental AutoImmune Uveitis (SAG-EAU and IRBP-EAU, respectively).

DA and LEW rats are also addiction-prone to various drugs of abuse, such as Cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction.

By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction.

Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in HypoThalamic-Pituitary-Adrenal (HPA) Axis function.

For example, circadian production of CorticoSteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in CorticoSterone levels.

Since CorticoSteroids potentially have significant influences on Immune function and AutoImmune Disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect Genetic control of these various phenotypic differences, focusing initially on the regulation of AutoImmune Disease expression.

Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and Streptococcal-Cell-Wall Arthritis (SCWA)], we have identified, to date, 14 genomic regions [Quantitative Trait Loci (QTL)] that regulate disease expression in these crosses.

Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among AutoImmune disease susceptibility, drug addiction, and HPA axis and stress response function.

These initial data, however, indicate that the Genetic control of the AutoImmune disease traits is highly complex.

Cannabinoids, the active components of Cannabis sativa (Marijuana), and their derivatives produce a wide spectrum of Central and Peripheral effects, some of which may have clinical application.

The discovery of specific Cannabinoid receptors and a family of endogenous Ligands of those receptors has attracted much attention to Cannabinoids in recent years. One of the most exciting and promising areas of current Cannabinoid research is the ability of these compounds to control the cell survival/death decision.

Thus Cannabinoids may induce proliferation, growth arrest, or Apoptosis in a number of cells, including Neurons, Lymphocytes, and various transformed Neural and NonNeural Cells.

The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined.

Regarding the Central Nervous System, most of the experimental evidence indicates that Cannabinoids may protect Neurons from toxic insults such as Glutamaergic overstimulation, Ischemia and Oxidative damage.

In contrast, Cannabinoids induce apoptosis of Glioma Cells in culture and regression of malignant Gliomas in vivo. Breast and Prostate Cancer Cells are also sensitive to Cannabinoid-induced antiproliferation.

Regarding the Immune System, low doses of Cannabinoids may enhance cell proliferation, whereas high doses of Cannabinoids usually induce growth arrest or Apoptosis.

The NeuroProtective effect of Cannabinoids may have potential clinical relevance for the treatment of NeuroDegenerative Disorders such as Multiple Sclerosis, Parkinson's Disease, and Ischemia/Stroke.

Whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant Brain Tumors.

Ongoing investigation is in search for Cannabinoid based therapeutic strategies devoid of nondesired Psychotropic effects.

Cognate interactions between human adult Microglia and activated T-Lymphocytes induce the production of inflammatory Cytokines.

Since this interaction can occur in a Non-Antigen-dependent manner, it is relevant to a variety of CNS diseases where activated T-Cells, regardless of specificities, come into contact with Microglia.

These disorders include Multiple Sclerosis, Trauma, Stroke and Alzheimer's Disease.

A model cell line would facilitate studies of the engagement between T-Cells and human adult Microglia, since the latter are difficult to obtain in substantial quantity or frequency.

This study shows that the PMA/IFN-gamma-treated U937 cell line shows similarities to Microglia in its interaction with activated T-Lymphocytes, in that the production of Tumor Necrosis Factor-alpha (TNF-), InterLeukin (IL-4), IL-10 and IL-12 is induced.

Morphological features and mechanisms of Cytokine production resemble those observed in Microglia T-Cell co-cultures since CTLA-4 and CD40-CD40L blockades reduce TNF- and IL-10 levels, while anti-CD23 inhibits IL-10 only in U937-T-Cell interactions.

We propose that PMA/IFN-γ-treated U937 cells can serve as a model of human adult Microglia to study Cytokine generation in response to interactions with activated T-Cells.

The success of Diffusion Magnetic Resonance Imaging (MRI) is deeply rooted in the powerful concept that during their random Diffusion-driven displacements, molecules probe tissue structure at a microscopic scale well beyond the usual image resolution.

As Diffusion is truly a three-dimensional process, molecular mobility in tissues may be Anisotropic, as in Brain White Matter.

With Diffusion Tensor Imaging (DTI), Diffusion Anisotropy effects can be fully extracted, characterized, and exploited, providing even more exquisite details on tissue microstructure.

The most advanced application is certainly that of fiber tracking in the Brain, which, in combination with functional MRI, might open a window on the important issue of connectivity.

DTI has also been used to demonstrate subtle abnormalities in a variety of diseases (including Stroke, Multiple Sclerosis, Dyslexia, and Schizophrenia) and is currently becoming part of many routine clinical protocols.

The aim of this article is to review the concepts behind DTI and to present potential applications.

Copyright 2001 Wiley-Liss, Inc.

A differential morphological response of mature Oligodendrocytes (OL) isolated from human and pig Brains to the phorbol ester 12-O-TetradecanoylPhorbol-13-Acetate (TPA) and to the Nerve Growth Factor (NGF) was observed.

In both cases, OL regenerate their processes; however, the rate and the extension of the process formation of human OL were behind that of pig OL.

Presumably, the advanced age of the human tissue in these experiments might have contributed to this decrease in process formation, an effect that was already observed for rat OL [Yong et al. (1991) J NeuroSci Res 29:87-99].

The less effectivity of NGF via TrkA, which was ImmunoCytoChemically shown in human OL, and of TPA via the Protein Kinase C (PKC) pathway, may have its common focus on the Mitogen-Activated Protein Kinase (MAPK) cascade. In this context, it was noted that only a few studies on aging of mature OL are available.

It is conceivable that age-related changes in the properties of OL could be an important factor for their Cellular responsiveness during longer lasting DeMyelinating Diseases such as Multiple Sclerosis.

Hence, this review would like to provide a basis for future investigations on the aging of mature OL. The data presently available suggest a preliminary classification of mature OL into three categories.

Copyright 2001 Wiley-Liss, Inc.

Multiple Sclerosis (MS) is an inflammatory disorder of the Central Nervous System (CNS), characterized by Focal destruction of Myelin.

Although it is evident that the Immune System contributes to tissue destruction in MS, it is still unclear as to whether this Immune Response is a cause or a consequence of the disease process.

In addition, there is debate over the contribution of Axonal damage to clinical progression.

We have described a murine model of Relapsing/Remitting MS (RR-MS), the most common form of the disease, following Immunization with the Myelin component, Myelin Oligodendrocyte Glycoprotein (MOG).

We showed that a single injection of a MOG peptide (MOG(35-55)) in NOD/Lt mice induces a Paralytic relapsing disease with extensive plaque-like DeMyelination. This model also mimics many of the Immunological features associated with RR-MS.

To investigate the relationship between clinical episodes, inflammation, and DeMyelination/ReMyelination, we analyzed Lesions.

During each attack and remission over the course of the disease, using Histological, ImmunoCytoChemical, and Electron Microscopy (EM) techniques.

We show that Morphological features of lesions in our model resemble those observed in MS.

Indeed, severe inflammation and DeMyelination coincide with the peak of clinical episodes while remissions are characterized by quiescent plaques.

Furthermore, Axonal damage is evident from the earliest stage of the disease and increases in severity with subsequent relapses.

These data establish that in the model of MS-like disease, the peak of clinical episodes coincides with severe inflammation and DeMyelination and that Axonal pathology correlates with clinical progression.

Copyright 2001 Wiley-Liss, Inc.