The Cellular Immunology Of Multiple Sclerosis
Al-Omaishi J, Bashir R, Gendelman HE
J Leukoc Biol 1999 Apr;65(4):444-52
The Center for NeuroVirology and Neurodegenerative Disorders, The Dept of Pathology, Section of Neurology,
Univ of Nebraska Medical Center, Omaha 68198-5215, USA
PMID# 10204572; UI# 99219266
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 Response Heterogeneity: Activation Of A Pro-Inflammatory Response By Interferon and ß. A Possible Basis For Diverse Responses To Interferon-ß In MS
Jansen M, Reinhard JF Jr
J Leukoc Biol 1999 Apr;65(4):439-43
Glaxo Wellcome, Inc., Dept of Molecular Pharmacology, Research Triangle Park, North Carolina, USA
PMID# 10204571; UI# 99219265
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.
Correlation Between MRI And Short-Term Clinical Activity In Multiple Sclerosis: Comparison Between Standard- And Triple-Dose Gd-Enhanced MRI
Rovaris M, Rodegher M, Comi G, Filippi M
Eur Neurol 1999 Apr;41(3):123-127
Univ of Milan, NeuroImaging Research, Dept of NeuroScience, IRCCS Ospedale San Raffaele, Milan, Italy
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.
Cross-Reactivity Of T-Cell Clones Specific For Altered Peptide Ligands Of Myelin Basic Protein
Ausubel LJ, Bieganowska KD, Hafler DA
Cell Immunol 1999 Apr 10;193(1):99-10
Center for Neurologic Diseases, Laboratory of Molecular Immunology, Boston, Massachusetts, 02115
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.
IL-12-Mediated NKRP1A Up-Regulation And Consequent Enhancement Of Endothelial TransMigration Of Vdelta2+ TCRdelta+ T-Lymphocytes
From Healthy Donors And Multiple Sclerosis Patients
Poggi A, Zocchi MR, Costa P, Ferrero E, Borsellino G, Placido R, Galgani S, Salvetti M, Gasperini C, Ristori G, Brosnan CF, Battistini L
J Immunol 1999 Apr 1;162(7):4349-4354
Laboratorio Immunopatologia, Istituto Nazionale per la Ricerca sul Cancro e Centro Biotecnologie Avanzate (IST-CBA), Genoa, Italy; Laboratorio Immunologia dei Tumori, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy; Laboratorio NeuroImmunologia, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia, Rome, Italy; Dipartimento di NeuroScienze "Lancisi," Ospedale S. Camillo, Rome, Italy; Dipartimento di Scienze Neurologiche,
Universita' "La Sapienza," Rome, Italy; and Dept of Pathology, Albert Einstein College of Medicine, Bronx, NY
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.
Measuring Change In Disability
After Inpatient Rehabilitation
Comparison of the responsiveness of the Barthel index and the Functional Independence Measure
van der Putten JJ, Hobart JC, Freeman JA, Thompson AJ
J Neurol NeuroSurg Psychiatry 1999 Apr;66(4):480-4
Institute of Neurology, London, UK
PMID# 10201420; UI# 99215603
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.
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.
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.
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.
Statistical Power Of MRI Monitored Trials
In Multiple Sclerosis
New data and comparison with previous results
Sormani MP, Molyneux PD, Gasperini C, Barkhof F, Yousry TA, Miller DH, Filippi M
J Neurol NeuroSurg Psychiatry 1999 Apr;66(4):465-9
Univ of Milan, Dept of NeuroScience, Scientific Institute, Ospedale San Raffaele, Italy
PMID# 10201417; UI# 99215600
To evaluate the durations of the follow up and the reference population sizes needed to achieve optimal and stable statistical powers for two period cross over and parallel group design clinical trials in Multiple Sclerosis.
When using the numbers of new enhancing lesions and the numbers of active scans as end point variables.
The statistical power was calculated by means of computer simulations performed using MRI data obtained from 65 untreated Relapsing/Remitting or Secondary/Progressive patients who were scanned monthly for 9 months.
The statistical power was calculated for follow up durations of 2, 3, 6, and 9 months and for sample sizes of 40-100 patients for parallel group and of 20-80 patients for two period cross over design studies.
The stability of the estimated powers was evaluated by applying the same procedure on random subsets of the original data.
When using the number of new enhancing lesions as the end point, the statistical power increased for all the simulated treatment effects.
With the duration of the follow up until 3 months for the parallel group design and until 6 months for the two period cross over design.
Using the number of active scans as the end point, the statistical power steadily increased until 6 months for the parallel group design and until 9 months for the two period cross over design.
The power estimates in the present sample and the comparisons of these results with those obtained by previous studies with smaller patient cohorts suggest that.
Statistical power is significantly overestimated when the size of the reference data set decreases for parallel group design studies or the duration of the follow up decreases for two period cross over studies.
These results should be used to determine the duration of the follow up and the sample size needed when planning MRI monitored clinical trials in Multiple Sclerosis.
Axonal Cytoskeleton Changes In
Experimental Optic Neuritis
Zhu B, Moore GR, Zwimpfer TJ, Kastrukoff LF, Dyer JK, Steeves JD, Paty DW, Cynader MS
Brain Res 1999 Apr 10;824(2):204-217
Vancouver Hospital and Health Science Center, Dept of Ophthalmology,
Univ of British Columbia, 2550 Willow Street, Vancouver, British Columbia, Canada
Axonal loss and degeneration in Multiple Sclerosis (MS) and Experimental Allergic EncephaloMyelitis (EAE) have been suggested by Brain imaging, pathological and Axonal transport studies.
Further elucidation of the processes and mechanisms of Axonal degeneration in DeMyelinating Diseases is therefore of potential importance in order to alleviate the permanent disabilities of MS patients.
However, detailed studies in this area are impeded by the small number of reliable models in which the onset and location of DeMyelination can be well-controlled.
In this study, microinjection of polyclonal rabbit Anti-GalactoCerebroside (anti-Gal C) AntiBody and guinea pig Complement was used to induce local DeMyelination in the rat optic nerve.
We found that treatment with appropriate volumes of the AntiBody and Complement could induce local DeMyelination with minimal pressure or trauma-induced damage.
Local changes in NeuroFilaments (NFs) and MicroTubules (MTs) were examined with both ImmunoHistoChemistry (IHC) and Electron Microscopy (EM).
On day 1 after microinjection, we observed moderate NF and MT disassembly in the local DeMyelinated area, although in most cases, no apparent inflammatory cell infiltration was seen.
The NF and MT changes became more apparent on days 3, 5, 7 after microinjection, along with gradually increased inflammatory cell infiltration.
These results suggested that acute DeMyelination itself may induce local cytoskeleton changes in the DeMyelinated Axons, and that the ensuing local Inflammation may further enhance the Axonal damage.
When the lesions were stained with specific AntiBodies for T-Lymphocytes, Macrophages, and Astrocytes, we found that most of the cells were Macrophages.
Suggesting that Macrophages may play a greater role in inflammation-related Axonal degeneration and Axonal Loss.
These results were confirmed and further characterized on the ultrastructural level.
Copyright 1999 Elsevier Science B.V.