Cellular And Humoral Immune Responses Against AutoReactive T-Cells In Multiple Sclerosis After T-Cell Vaccination
Hermans G, Denzer U, Lohse A, Raus J, Stinissen P
J AutoImmun 1999 Sep;13(2):233-246
Limburgs Universitair Centrum, AutoImmune Disease Unit, Dr L. Willems-Instituut,
UnivCampus, Diepenbeek, Belgium
Myelin Basic Protein (MBP)-reactive T-Cells may play an important role in the AutoImmune PathoGenesis of Multiple Sclerosis (MS).
MBP-reactive T-Cells can be specifically targeted by T-Cell vaccination, a procedure whereby MS patients are immunized with attenuated autologous MBP reactive T-Cells.
T-Cell vaccination induces Immune responses to the Vaccine Cells together with a depletion of MBP reactive T-Cells.
Forty-nine MS patients were treated with T-Cell vaccination in an extended phase I trial to study the safety, Immune responses and clinical effects of T-Cell vaccination.
In the present paper the Immune responses towards the Vaccine Cells were characterized. Substantial long-term in vitro proliferative responses were observed in all treated patients.
Some patients, immunized with different clones, displayed distinct proliferative reactivity against the various vaccine clones, suggesting unequal ImmunoGenic properties of these clones.
Reactive TCRalphaB(+), CD8+and CD4+T-Cells, and to a lesser extent, delta T-Cells and NK cells were observed to in vitro stimulation with the Vaccine Cells.
A small fraction only of CD8+T-Cells expressed cytolytic and inhibitory anti-clonotypic reactivity against the Vaccine Cells.
Stimulation with the vaccine clones predominantly induced expression of pro-inflammatory Cytokines in these mixed cultures, although one vaccine clone consistently induced production of IL-4.
CD4+T-Cells are the major Cytokine-producing cells in these Anti-Vaccine lines.
We could not detect upregulated AntiBody responses to the Vaccine Cells in most patients, although a temporary AntiBody response was observed in one patient.
In conclusion, immunization with attenuated AutoReactive T-Cells induces a complex cellular response specifically targeted at the Vaccine Cells, but no AntiBody responses.
These data provide further insights into the mechanisms of T-Cell vaccination and improve our understanding of the complex regulatory networks of AutoReactive T-Cells.
Copyright 1999 Academic Press.
A Multidimensional Assessment Of Multiple Sclerosis: Relationships Between Disability Domains
Provinciali L, Ceravolo MG, Bartolini M, Logullo F, Danni M
Acta Neurol Scand 1999 Sep;100(3):156-62
Univ of Ancona, Neurorehabilitation Clinic, Italy
PMID# 10478578; UI# 99405683
- To test the feasibility of a multidimensional assessment based on both task-related and self-evaluation questionnaire scores in patients with Multiple Sclerosis (MS);
- To correlate the results from selective measures with the severity of illness in terms of the Expanded Disability Status Scale (EDSS) score;
- To assess the relationships between different domains of MS-related Disability and Handicap.
Patients & Methods
Eighty-three MS patients (M/F 31/52; age 43.26 +/- 10.9 years, range 21-72) underwent a standard clinical evaluation of motor abilities (by means of the Rivermead Mobility index, Timed Walking Test, Nine Hole Peg test and Hauser Ambulation Index) and Cognitive performances (using Digit Symbol, Buschke-Fuld selective remind test, "FAS"-Word Fluency, Wisconsin Card Sorting test and Block design test).
The Beck Depression inventory, MS Specific Fatigue Scale, Functional Assessment of MS and London Handicap Scale were applied to evaluate Mood, Fatigue, Quality of Life and Handicap, respectively.
Minimal Record of Disability measures - MRD (i.e. EDSS, Inability Status Scale and Environmental Status Scale) were also applied to test the criterion validity of the selected Disability and Handicap scales.
The Kruskal-Wallis H-test for independent samples tested differences between subgroups with an increasing EDSS score (<3.5, 3.5-6.0, >6.0).
The covariance and redundancy of measures included in the multidimensional assessment were evaluated through Factor Analysis.
The Multiple Regression Analysis was used to detect the relative impact of either Motor or Cognitive Disabilities and depression on handicap and quality of life.
The multimodal assessment took 70 min on average to be performed, being well accepted by patients.
Motor abilities worsened as the EDSS score rose, unlike Cognitive performances which proved to be similarly impaired at different severity levels. Measures of Fatigue and Depression were not related to EDSS values.
The chosen measures were assigned by Factor Analysis to 4 domains corresponding to motor performance, executive performance, Cognitive abilities and quality of life, respectively.
Regression analysis showed how Handicap and Depression independently affect quality of life.
While the Handicap score is mostly influenced by Motor ability, as measured by the Rivermead Mobility Index, the Depression score grows independently of any physical or Cognitive disability and seems to be related to Fatigue self-assessment scores.
A multidimensional approach to MS patient assessment allows a more detailed and sensitive evaluation of their Disability profile and perceived difficulties, leading to a care programme tailored to the patient's needs.
A Health-Related Quality Of Life Questionnaire
For Multiple Sclerosis
Pfennings LE, Van der Ploeg HM, Cohen L, Bramsen I, Polman CH, Lankhorst GJ, Vleugels L
Acta Neurol Scand 1999 Sep;100(3):148-55
Vrije Universiteit, Dept of Medical Psychology, Amsterdam, The Netherlands
PMID# 10478577; UI# 99405682
The construction of a brief, valid and reliable HRQoL questionnaire for use in Multiple Sclerosis patients based on generic and disease-specific HRQoL measures.
Material & Methods
The Medical Outcomes Study 36-item Short Form Health Survey (SF-36), COOP/ WONCA Charts, and Disability & Impact Profile (DIP) were used in a longitudinal study in 162 patients with Multiple Sclerosis.
Factor analyzes identified 2 underlying dimensions of HRQoL, relating to "physical functioning" and "psychological functioning".
Selection of the 3 highest loading reliable scales on each factor resulted in a final questionnaire consisting of 3 scales of the SF-36 and 3 scales of the DIP. In total 40 items were selected; completion time is about 10 min.
The final questionnaire adequately measured 2 dimensions of HRQoL. The length of the questionnaire is acceptable for patients with MS in view of respondent burden.
Agius MA, Kirvan CA, Schafer AL, Gudipati E, Zhu S
Acta Neurol Scand 1999 Sep;100(3):139-47
Univ of California at Davis, 95616, USA
PMID# 10478576; UI# 99405681
The presence of T-cell reactivity to alphaB-Crystallin in patients with Multiple Sclerosis (MS) has suggested that this small molecular weight Heat shock protein (Hsp) may be an AutoAntigen in MS.
Material & Methods
We have tested the Serum of patients with Clinically Definite MS (n=30), Other Inflammatory Neurological Disease (n=22), Non-Inflammatory Neurological Disease (n=42) and healthy individuals (n=23) for Systemic Humoral Responses to bovine alphaB-Crystallin, to the homologous chaperone protein, A-Crystallin, and to another small Hsp, Hsp 27.
Sixty-three percent of MS patients exhibited Immunoreactivity to -Crystallin and this was present in all 4 of 4 non-ambulatory patients with MS.
In contrast, Serum concentrations in MS patients of AntiBodies to the small Hsp, Hsp27, and to Myelin Basic Protein were negligible (P<0.001).
Serum anti--Crystallin Immune responses were detected in significantly lower percentages of patients with Other Inflammatory Neurological Diseases (32%, P<0.025), and with Non-Inflammatory Neurological Diseases (12%, P<0.001).
None of the healthy control individuals showed anti--Crystallin reactivity. The concentration of anti--crystallin AntiBodies in patients with MS correlated with severe disease (P<0.05) and with active disease (P<0.025).
Our observations support the notion that anti--Crystallin AutoImmune responses may contribute to Pathogenicity in MS and may represent a mechanism of how recurrent attacks of MS develop subsequent to an isolated DeMyelinating episode.
Brain Lesions: When Should FAIR Sequences Be Used In MR Evaluation?
Okuda T, Korogi Y, Shigematsu Y, Sugahara T, Hirai T, Ikushima I, Liang L, Takahashi M
Radiology 1999 Sep;212(3):793-8
Kumamoto Univ, School of Medicine, Dept of Radiology, Japan
PMID# 10478248; UI# 99407686
To compare qualitatively and quantitatively the contrast of Brain lesions detected with Fluid-Attenuated Inversion-Recovery (FLAIR) and intermediate-weighted sequences at Magnetic Resonance (MR) Imaging.
Materials & Methods
In this prospective study, 47 patients suspected of having a Brain lesion underwent MR imaging with FLAIR, intermediate-weighted, and T2-weighted sequences.
Qualitative assessment was performed of lesion conspicuity, detection, overall image artifact, and additional clinical information.
Contrast and contrast-to-noise ratio (CNR) were calculated between lesions and the normal Brain or CerebroSpinal Fluid (CSF).
FLAIR images were equal to intermediate-weighted images for overall lesion conspicuity and detection but were associated more often with image artifacts.
Lesion-to-background contrast was significantly higher on FLAIR than on intermediate-weighted images. FLAIR images failed to demonstrate Multiple Sclerosis (MS) plaques located in the Basal Ganglia and BrainStem.
Although FLAIR images provided additional information in some cases, they did not have distinct advantages over intermediate-weighted images.
When cases of MS are evaluated, intermediate-weighted images are preferable to FLAIR images. Except in cases of MS, either FLAIR or intermediate-weighted sequences should be added to T2-weighted sequences at MR imaging.
Analysis Of Gene Expression In Mutiple Sclerosis Lesions Using cDNA Microarrays
Whitney LW, Becker KG, Tresser NJ, Caballero-Ramos CI, Munson PJ, Prabhu VV, Trent JM, McFarland HF, Biddison WE
Ann Neurol 1999 Sep;46(3):425-8
National Institutes of Health, National Institute of Neurological Disorders and Stroke, NeuroImmunology Branch, Molecular Immunology Section, Bethesda, MD 20892-1400, USA
PMID# 10482277; UI# 99410003
In Multiple Sclerosis (MS) patients, a coordinated attack of the Immune System against the primary constituents of Oligodendrocytes and/or the Myelin sheath of Oligodendrocytes results in the formation of lesions in the Brain and Spinal Cord.
Thus far, however, a limited number of Genes that potentially contribute to lesion pathology have been identified.
Using cDNA microarray technology, we have performed experiments on MS tissue monitoring the expression pattern of over 5,000 Genes and compared the Gene expression profile of normal White Matter with that found in acute lesions from the Brain of a single MS patient.
Sixty-two differentially expressed Genes were identified, including the Duffy chemokine receptor, Interferon regulatory factor-2, and Tumor Necrosis Factor receptor-2 among others.
Thus, cDNA microarray technology represents a powerful new tool for the identification of Genes not previously associated with the MS disease process.
Migratory Behavior Of Lymphocytes In MS
Effects Of Interferon-ß-1b Therapy
Uhm JH, Dooley NP, Stuve O, Francis GS, Duquette P, Antel JP, Yong VW
Ann Neurol 1999 Sep;46(3):319-24
Montreal Neurological Hospital and Institute, McGill University, Dept of NeuroImmunology, Quebec, Canada
PMID# 10482262; UI# 99409988
Previous reports by our group and by others have shown that in vitro treatment of T-Cells derived from healthy, normal subjects with Interferon beta-1b (IFN-ß-1b) reduces MetalloProteinase (MetalloProteinase type 9 [MMP-9]) activity with a consequent reduction in Lymphocyte migration.
In this study, we used a Boyden chamber assay to assess the migratory capacity of T-Cells derived from Multiple Sclerosis patients who either did or did not receive ß-1b.
Lymphocytes derived from patients treated for less than 2 years with ß migrated at a low rate that was indistinguishable from that of cells isolated from healthy donors.
However, longer term treatment with IFN (>3.5 years) was associated with a reversion of the migration to a high level that did not differ statistically from that of cells isolated from untreated Multiple Sclerosis patients.
For both high-migratory groups, migration could be reduced to control levels after the exogenous addition of TIMP-1, a relatively specific inhibitor of the MMP-9, implicating this protease in the process of T-cell migration.
Our findings suggest that one of the mechanisms by which ß exerts its action is by reducing MMP-9 activity and thus the entry of inflammatory cells into the Nervous System and, as such, MMPs may constitute potential therapeutic targets in inflammatory diseases such as Multiple Sclerosis.