In Vitro Modulation Of Adhesion Molecules, Adhesion Phenomena, And Fluid Phase Endocytosis On Human Umbilical Vein Endothelial Cells And Brain-Derived MicroVascular Endothelium By IFN-ß-1a
Defazio G, Gelati M, Corsini E, Nico B, Dufour A, Massa G, Salmaggi A
J Interferon Cytokine Res 2001 May;21(5):267-72
Istituto di Clinica Neurologica, Universita di Bari, Policlinico, Bari, Italy
PMID# 11429156; UI# 21322528
Administration of Interferon-beta (IFN-ß) In Multiple Sclerosis (MS) patients provides clinical benefits, although its mechanism(s) of action are not completely understood.
We addressed the issue of whether concentrations of IFN-ß-1a close to those reached in the Serum of treated MS patients could modulate either Adhesion Molecules or adhesion of Peripheral Blood MonoNuclear Cells (PBMC).
As well as Fluid Phase Endocytosis (FPE) in Human Umbilical Vein Endothelial Cells (HUVEC) and in Brain-derived Microvascular Endothelial Cells (HBMEC).
Adhesion was assessed by flow cytometry, and FPE was evaluated by Peroxidase uptake. In our study, 200 U/ml IFN-ß-1a induced a reduction in adhesion of PBMC to HUVEC.
The information reported herein may contribute to further elucidating some of the mechanisms of action of IFN-ß on Vascular Endothelium.
Conformational Analysis Of A GlycoSylated Human Myelin Oligodendrocyte Glycoprotein Peptide Epitope Able To Detect AntiBody Response In Multiple Sclerosis
Carotenuto A, D'Ursi AM, Nardi E, Papini AM, Rovero P
J Med Chem 2001 Jul 5;44(14):2378-81
Univ of Salerno, Dept of Pharmaceutical Sciences, I-84084 Fisciano, Italy; and Univ of Florence, Dept of Organic Chemistry "Ugo Schiff", I-50131 Florence, Italy
PMID# 11428934; UI# 21322574
Myelin Oligodendrocyte GlycoProtein (MOG), a minor Myelin component, is an important Central Nervous System specific target AutoAntigen for primary DeMyelination in AutoImmune Diseases such as Multiple Sclerosis (MS).
The native structure of MOG presents a GlycoSylation site at position 31 (Asn(31)). It has been recently described that GlycoSylation of a MOG Peptide Epitope improved the detection of specific AutoAntiBodies in Sera of MS patients.
The solution conformational behavior of two MOG derived Peptides-hMOG(30-50) (1) and the GlycoSylated analogue [Asn(31)(N-beta-Glc)]hMOG(30-50) (2)-were investigated through NMR analysis in a water/HFA solution.
Conformational studies revealed that Peptides 1 and 2 adopted similar conformations in this environment.
In particular, they showed strong propensity to assume a well-defined amphipatic structure encompassing residues 41-48. The N-terminal region resulted to be almost completely unstructured for both Peptides.
The presence in 1 of a low populated Asx-turn conformation characteristic of the Asn-Xaa-Thr GlycoSylation sites was the only conformational difference between Peptides 1 and 2.
Thus, the specific AntiBody recognition of Peptide 2 is most likely driven by direct interactions of the AntiBody binding site with the Asn-linked sugar moiety.
Use Of The Multiple Sclerosis Functional Composite As An Outcome Measure In A Phase 3 Clinical Trial
Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Jak AJ, Kniker JE, Kooijmans MF, Lull JM, Sandrock AW, Simon JH, Simonian NA, Whitaker JN
Arch Neurol 2001 Jun;58(6):961-967
The Mellen Center-U10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH
The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test).
The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of Interferon-beta-1a (Avonex) in patients with Secondary/Progressive MS.
To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure.
Examining technicians underwent formal training using standardized materials.
The MSFC was performed according to a standardized protocol.
The 436 patients enrolled in the International Multiple Sclerosis Secondary/Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization.
Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects.
The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90.
The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely.
Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of Neurologic function in patients with MS.
The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects.
The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.
Barkhof F, van Waesberghe JH, Filippi M, Yousry T, Miller DH, Hahn D, Thompson AJ, Kappos L, Brex P, Pozzilli C, Polman CH
Brain 2001 Jul;124(Pt 7):1396-1402
MR-MS center, VU Medical Centre, Amsterdam, the Netherlands;
Scientific Institute San Raffaele, Univ of Milan, NeuroImaging Research Unit, Dept of NeuroScience, Dept of Neurology, La Sapienza, Rome, Italy; Institut for Rontgendiagnostik, Dept of NeuroRadiology; Universitat Wurzburg, Klinikum Grosshadern, Munich, Germany; Institute of Neurology, NMR Research Group, London, UK; and Univ Hospitals, Kantonsspittal, Dept of Neurology, Basel, Switzerland
Recently, the clinical efficacy of Interferon-beta-1b (IFN-ß-1b) was demonstrated for Secondary/Progressive (SP) Multiple Sclerosis in a European multicenter study.
We evaluated the effect of IFN-beta-1b treatment on the rate of development of HypoIntense T1 MRI lesions, a putative marker of Axonal damage.
Unenhanced T1-weighted images were obtained in a subgroup of 95 Multiple Sclerosis patients from five centers at 6-month intervals.
This subgroup was similar to the total study population for all demographic, clinical and MRI parameters.
An experienced observer blinded to the clinical data and treatment allocation measured volumes.
The median baseline lesion load for HypoIntense T1 lesions was 5.1 cm(3) for placebo-treated and 4.9 cm(3) for IFN-ß-1b-treated patients (P = 0.56).
Placebo-treated patients showed an increase in T1 lesion load by a median of 14% per year (P = 0.0002 compared with baseline).
This was reduced to 7.7% per year in the IFN-ß-1b-treated patients (P = 0.003 versus placebo).
In the IFN-ß-1b arm there was a statistically significant correlation between absolute change in Expanded Disability Status Scale scores and T1 lesion load by month 36 (r = 0.38, P = 0.0015).
In patients with SP Multiple Sclerosis, IFN-ß-1b treatment reduces the development of HypoIntense T1 lesions, suggesting that reduced Axonal Damage in lesions may play a part in the beneficial effect that is observed clinically.