Multiple Approaches To Multiple Sclerosis
Nat Med 2000 Jan;6(1):15-16
Stanford University, Beckman Center for Molecular Medicine, B002, Dept . of Neurology and Neurological Sciences, Stanford, California 94305, USA
Multiple Sclerosis results from the failure of several different regulatory mechanisms designed to protect against AutoImmunity, suggesting multiple targets for therapeutic intervention.
Three papers in this issue suggest that if Tolerance to components of the Nervous System is not maintained in the Thymus and AutoImmunity ensues.
The extent of Brain damage can be checked by blockade of Glutamate receptors on Neurons and Oligodendrocytes (pages 56-70).
Anterior Uveitis In Murine Relapsing Experimental AutoImmune EncephaloMyelitis (EAE), A Mouse Model Of Multiple Sclerosis (MS)
Constantinescu CS, Lavi E
Curr Eye Res 2000 Jan;20(1):71-76
Univ of Leicester, Dept of Microbiology and Immunology,
To investigate whether Anterior Uveitis (AU), which often accompanies Central Nervous System (CNS) and Systemic Inflammatory Diseases including Multiple Sclerosis (MS), also develops in a murine Relapsing model of MS.
Experimental AutoImmune EncephaloMyelitis (EAE) closely resembling Relapsing/Remitting MS, induced by immunization with Myelin Basic Protein (MBP) in mice.
(PL/J x SJL) F1 female mice were immunized with MBP in Complete Freund's Adjuvant (CFA) using Pertussis Toxin as co-adjuvant.
EAE was scored clinically on a scale of 0-5 based on the degree of Paralysis. Uveitis was assessed by slit-lamp biomicroscopy. Histolological analysis of the CNS and Eye were performed.
All immunized mice developed a characteristic Relapsing Paralysis. Evidence of AU was present late in the course of EAE.
Only after the resolution of the first clinical relapse, in 4 of 5 mice (80%) (clinical evidence) and 5 of 5 (100%) (histological evidence).
AU was mild to moderate with the exception of one animal, in which it was severe. Involvement was invariably bilateral. Histology showed MonoNuclear inflitrates in the Iris and Ciliary Body.
Bilateral secondary Cataracts were observed in the animal with severe Inflammation. Paralytic episodes and the AU did not coincide.
There were no clinical or histological Eye abnormalities in control mice, either non-immunized or immunized with CFA and Pertussis Toxin only.
We report AU in a mouse model of EAE which strongly resembles Relapsing MS. These results further suggest shared Antigenic determinants between the CNS and the Eye.
Which likely become exposed to the Immune System late in the course of CNS Inflammation.
Smith KJ, Felts PA, John GR
Brain 2000 Jan;123(Pt 1):171-184
Guy's, King's and St Thomas' School of Medicine, NeuroInflammation Research Group, Dept of NeuroImmunology, Guy's Campus, London SE1 9RT, UK
Several clinical trials have demonstrated that 4-AminoPyridine (4-AP), a Potassium channel-blocking agent, improves symptoms in some patients with Multiple Sclerosis.
The beneficial effects have typically been attributed to the restoration of conduction to DeMyelinated Axons, since this effect was previously demonstrated experimentally.
However, the clinical dose is ~250-1000 times lower than that used experimentally, potentially making extrapolation of the experimental findings unreliable.
To examine the action(s) of 4-AP in DeMyelinating Disorders, the drug was administered at clinical doses, both in vivo and in vitro.
To rat Dorsal Column Axons which had been experimentally DeMyelinated by the IntraSpinal injection of Ethidium Bromide.
4-AP had no consistent effect in restoring conduction to DeMyelinated Axons, even to Axons which were held just on the verge of conducting by adjusting the lesion temperature.
However, 4-AP had prominent effects that did not involve DeMyelinated Axons, including the potentiation of Synaptic Transmission and an increase in skeletal muscle twitch tension.
We propose that these latter effects may be largely responsible for the beneficial action of 4-AP in Multiple Sclerosis patients.
If so, the dominant effects of 4-AP in Multiple Sclerosis patients are independent of DeMyelination, and it follows that 4-AP may be beneficial in other Neurological Disorders in which function is diminished.
Oligodendrocyte Survival, Loss And Birth In Lesions Of Chronic-Stage Multiple Sclerosis
Brain, Vol. 123, No. 1, 105-115, January 2000
Netherlands Institute for Brain Research, Graduate School NeuroSciences Amsterdam, Amsterdam, The Netherlands
One of the hallmarks of the human DeMyelinating Disease, Multiple Sclerosis is the inability to compensate adequately for the loss of Myelin and of Oligodendrocytes, the Myelin-forming cells of the CNS.
Oligodendrocyte Precursor Cells, a potential source of Oligodendrocytes, have been identified in lesions of chronic Multiple Sclerosis, but it is not known whether they develop into new, fully differentiated Oligodendrocytes, capable of ReMyelination.
Sections of post-mortem Multiple Sclerosis tissue were therefore ImmunoLabelled with AntiBodies to GalactoCerebroside (GalC).
The first Oligodendrocyte-specific molecule to be expressed by differentiating Oligodendrocyte Precursor Cells, and Myelin Oligodendrocyte Glycoprotein (MOG), a marker for mature Oligodendrocytes.
In total, 23 lesions from 15 subjects with Chronic Progressive Multiple Sclerosis were analyzed.
The ImmunoLabelling revealed that Chronic Multiple Sclerosis lesions contain only small numbers of immature, process-bearing, GalC-positive Oligodendrocytes (0-2 cells/mm(2) in 10 mum thick sections).
They had a relatively large, pale nucleus (maximum diameter: 9.9 +/- 0.9 mum).
Although they appeared to make contact with surrounding DeMyelinated Axons, most immature Oligodendrocytes appeared not to be engaged in Myelination.
These findings suggest that Oligodendrocyte differentiation of Precursor Cells is a rare event in Chronic Multiple Sclerosis, which is consistent with the general failure of Myelin repair during the later stages of this disease.
The lesions in the collection, in particular those with recent DeMyelinating activity, contained another distinct population of Oligodendrocytes.
It consisted of small, round cells with a small, dense nucleus (maximum diameter: 6.8 +/- 0.8 mum) that expressed both GalC and MOG but lacked processes.
Suggesting that these cells were mature Oligodendrocytes that had survived the loss of their Myelin sheaths, i.e. they were DeMyelinated Oligodendrocytes.
In the most recent lesions in the collection, the DeMyelinated Oligodendrocytes were found in large numbers throughout the center of the lesion (up to 700 cells/mm(2)).
While in the older lesions they were found only at the edges.
Moreover, when the borders of these older lesions still contained numerous Macrophages, they tended to contain more DeMyelinated Oligodendrocytes than those lacking Macrophages.
These findings suggest that mature, DeMyelinated Oligodendrocytes gradually disappear from lesion areas with increasing age of the lesion.
The present study thus suggests that the failure of Myelin repair, in at least some cases of Chronic Multiple Sclerosis is due to:
- Loss of DeMyelinated Oligodendrocytes from lesions
- Failure of the Oligodendrocyte Precursor population to expand and generate new Oligodendrocytes
Gaining further insight into these processes may prove crucial for the development of ReMyelination promoting strategies.
Macrophage-Derived Chemokine Production By Activated Human T-Cells In Vitro And In Vivo: Preferential Association With The Production Of Type 2 Cytokines
Galli G, Chantry D, Annunziato F, Romagnani P, Cosmi L, Lazzeri E, Manetti R, Maggi E, Gray PW, Romagnani S
Eur J Immunol 2000 Jan;30(1):204-210
Univ of Florence, Allergy, and Respiratory Disorders, Dept of Internal Medicine Section of Clinical Immunology, Florence, Italy
Macrophage-Derived Chemokine (MDC), a potent ChemoAttractant for chronically activated Th2 Lymphocytes, is constitutively expressed by Dendritic Cells, B-Cells, Macrophages, and Thymic Medullary Epithelial Cells, whereas Monocytes, NK Cells, and T-Lymphocytes produce MDC only upon appropriate stimulation.
In this study, we show in vitro MDC production also by activated T-Cells, which preferentially associate with the production of Th2 Cytokines, IL-4, IL-5, and IL-6.
And inversely correlate with the production of the Th1 Cytokine, IFN-.
Moreover, high levels of MDC were detected in the Sera of the great majority of subjects suffering from Mycosis Fungoides / Sezary Syndrome or Atopic Dermatitis, which are considered as disorders characterized by the predominant expansion and activation of Th2 Cells, respectively.
By contrast, Serum MDC levels in subjects with Multiple Sclerosis or Crohn's Disease, which are characterized by a Th1 predominance, did not differ significantly from those of healthy controls.
Finally, MDC expression was detected in the skin biopsy specimens of subjects with Atopic Dermatitis, where it was expressed by both Dendrite Cells and T-Lymphocytes.
Taken together, these findings suggest that MDC production by activated T-Cells may occur both in vitro and in vivo.
Particularly in association with Th2 Cytokines, thus providing an important amplification circuit for Th2-mediated responses.
Placebo Controlled Pilot Trial To Study The ReMyelinating Potential Of IntraVenous ImmunoGlobulins In Multiple Sclerosis
Stangel M, Boegner F, Klatt CH, Hofmeister C, Seyfert S
J Neurol NeuroSurg Psychiatry 2000 Jan;68(1):89-92
Universitatsklinikum Benjamin Franklin, Dept of Neurology, Freie Universitat Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany
Currently there is no treatment available to improve a stable deficit in Multiple Sclerosis.
It was shown in animal models that IntraVenous ImmunoGlobulins (IVIg) can enhance Central Nervous ReMyelination, and the first open trials were promising.
We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with Multiple Sclerosis with a stable clinical deficit.
The primary outcome parameter was the change in Central Motor Conduction Time as an indirect measure of Central Myelination.
Secondary outcome parameters were Neurological examinations including the Expanded Disability Status Scale (EDSS), Neurological Rating Scale (NRS), and Manual Muscle Testing (MMT).
Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks.
There was no difference in the Central Motor Conduction Times measured before and 6 weeks after each treatment.
Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo.
In conclusion, our data do not support a role for IVIg in the ReMyelination of stable Multiple Sclerosis lesions as measured by Central Conduction Time. The importance of the small clinical benefit is currently not clear.
MicroVascular Decompression For Trigeminal Neuralgia: Comments On A Series Of 250 Cases, Including 10 Patients With Multiple Sclerosis
Broggi G, Ferroli P, Franzini A, Servello D, Dones I
J Neurol NeuroSurg Psychiatry 2000 Jan;68(1):59-64
Istituto Nazionale Neurologico C. Besta, Dept of NeuroSurgery, Milan, Italy
To examine surgical findings and results of MicroVascular Decompression (MVD) for Trigeminal Neuralgia (TN), including patients with Multiple Sclerosis.
To bring new insight about the role of MicroVascular Compression in the PathoGenesis of the disorder and the role of MVD in its treatment.
Between 1990 and 1998, 250 patients affected by Trigeminal Neuralgia underwent MVD in the Dept of NeuroSurgery of the "Istituto Nazionale Neurologico C Besta" in Milan.
Limiting the review to the period 1991-6, to exclude the "learning period" (the first 50 cases) and patients with less than 1 year follow up, surgical findings and results were critically analyzed in 148 consecutive cases, including 10 patients with Multiple Sclerosis.
Vascular Compression of the Trigeminal Nerve was found in all cases.
The recurrence rate was 15.3% (follow up 1-7 years, mean 38 months). In five of 10 patients with Multiple Sclerosis an excellent result was achieved (follow up 12-39 months, mean 24 months).
Patients with TN for more than 84 months did significantly worse than those with a shorter history (p<0.05).
There was no mortality and most complications occurred in the learning period. Surgical complications were not related to age of the patients.
AetioPathoGenesis of Trigeminal Neuralgia remains a mystery.
These findings suggest a common NeuroModulatory role of MicroVascular Compression in both patients with or without Multiple Sclerosis rather than a direct causal role.
MVD was found to be a safe and effective procedure to relieve typical TN in patients of all ages.
It should be proposed as first choice surgery to all patients affected by TN, even in selected cases with Multiple Sclerosis, to give them the opportunity of pain relief without Sensory deficits.