Association Of Two Variants In IL-1beta and IL-1 Receptor Antagonist Genes With Multiple Sclerosis
Kantarci OH, Atkinson EJ, Hebrink DD, McMurray CT, Weinshenker BG
J NeuroImmunol 2000 Jul 1;106(1-2):220-227
Mayo Clinic and Foundation, Dept of Neurology, 200 First Street, SW, Rochester, MN, USA
We studied the putative association of a C-->T PolyMorphism in exon-5 of IL-1ß and an 85 bp tandem repeat in intron-4 of IL-1 Receptor antagonist (IL-1ra) Genes with susceptibility to or outcome of MS.
DNA from 122 cases from a population-based cohort in Olmsted County, MN who were previously categorized for disease severity and temporal course and 244 ethnically-matched controls were analyzed.
There was no association between either PolyMorphism and disease susceptibility. Allele-2 of IL-1ß and Allele-3 of the IL-1ra PolyMorphisms were associated with a favorable outcome (P=0.023 and P=0.030).
Lu F, Selak M, O'Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B
J Neurol Sci 2000 Aug 15;177(2):95-103
MS 406 MCP-Hahnemann University, Dept of Neurology, 245 North 15th Street, 19102, Philadelphia, PA, USA
Soluble products of activated Immune Cells include Reactive Oxygen Species (ROS) and Nitric Oxide (NO) with a high potential to induce biochemical modifications and degenerative changes in areas of inflammation in the Central Nervous System (CNS).
Previously, we demonstrated an increased production of ROS by activated MonoNuclear Cells (MNC) of patients with Multiple Sclerosis (MS) compared to those of controls, and development of Oxidative damage to total DNA in association with inflammation in chronic active plaques.
The current study aimed to determine whether Mitochondrial (mt) DNA is affected by Oxidative damage, and whether Oxidative damage to Mitochondrial macromolecules (including mt DNA) is associated with a decline in the activity of Mitochondrial enzyme complexes.
Using molecular and biochemical methods we demonstrate a trend for impaired NADH DeHydrogenase (DH) activity and a possible compensatory increase in complex IV activity in association with Oxidative damage to mt DNA in chronic active plaques.
ImmunoHistoChemistry confirms the increase of Oxidative damage to DNA predominantly located in the Cytoplasmic compartment of cells in chronic active plaques.
These observations suggest that Oxidative damage to macromolecules develops in association with inflammation in the CNS, and may contribute to a decline of energy metabolism in affected cells.
As observed in NeuroDegenerative Diseases of non-inflammatory origin, decreased ATP synthesis can ultimately lead to cell death or degeneration.
Therefore, elucidation of this pathway in MS deserves further studies which may identify NeuroProtective strategies to prevent tissue degeneration and the associated clinical disability.
Insulin-Like Growth Factor-1 Fails To Enhance Central Nervous System Myelin Repair During AutoImmune DeMyelination
Cannella B, Pitt D, Capello E, Raine CS
Am J Pathol 2000 Sep;157(3):933-943
Albert Einstein College of Medicine, Depts of Pathology (NeuroPathology), Neurology, and NeuroScience, Bronx, New York, and Univ of Genova, Genoa, Italy
Previous studies have shown that Insulin-like Growth Factor-1 (IGF-1) has beneficial effects, both clinically and HistoPathologically, on Experimental AutoImmune EncephaloMyelitis (EAE), although results vary depending on species and treatment regimen.
The present study investigated whether IGF-1, delivered at different time points during the acute and chronic phases of adoptively transferred EAE in SJL mice, had the ability to affect or enhance Myelin regeneration.
Central Nervous System tissue sampled at different stages of treatment was subjected to detailed NeuroPathological, ImmunoCytoChemical and molecular analysis.
The results revealed some transient clinical amelioration and low level ReMyelination after IGF-1 administration during the acute phase of EAE.
However, Central Nervous System tissue from acute phase treated animals sampled at chronic time points and from animals given IGF-1 during the chronic phase revealed no enhancing effect on ReMyelination in comparison to vehicle-treated controls.
Examination of Oligodendrocyte progenitor populations also revealed no differences between IGF-1- and vehicle-treated groups.
At the Cytokine level, the ImmunoModulatory molecules TGF-ß2 and TGF-ß3 displayed significant decreases that may have contributed to the transient nature of the effect of IGF-1 on EAE.
Together with evidence from previous studies, it appears doubtful that IGF-1 is a good candidate for treatment in Multiple Sclerosis, for which EAE serves as a major model.
A Phase I Trial Of Solubilized DR2:MBP84-102 (AG284) In Multiple Sclerosis
Goodkin DE, Shulman M, Winkelhake J, Waubant E, Andersson P, Stewart T, Nelson S, Fischbein N, Coyle PK, Frohman E, Jacobs L, Holcenberg J, Lee M, Mocci S
Neurology 2000 Apr 11;54(7):1414-20
Univ of California at San Francisco/Mt. Zion Multiple Sclerosis Center, Dept of Radiology; Anergen, Inc., Redwood City, CA.
PMID# 10751249; UI# 20215043
To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human Leukocyte Antigen-DR2 with Myelin Basic Protein84-102 (AG284)in patients with Secondary/Progressive MS.
Soluble species-specific Major Histocompatibility Complex Myelin Basic Protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with Chronic Relapsing Experimental Allergic EncephaloMyelitis.
Preincubation with AG284 reduces the proliferative response of a DR2-restricted, Myelin Basic Protein84-102-reactive T-Cell clone, derived from a MS patient, to Myelin Basic Protein84-102 in the presence of autologous Antigen-Presenting Cells.
Thirty-three patients with Secondary/Progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study.
The Primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment Gadolinium-enhanced Brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores.
The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new Gadolinium-enhancing MRI lesions.
AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.