Prevention Of A Chronic/Progressive Form Of EAE By An AntiBody Against Mucosal Cell Adhesion Molecule-1
Kanwar JR, Kanwar RK, Wang D, Krissansen GW
Immunol Cell Biol 2000 Dec;78(6):641-645
Univ of Auckland, School of Medicine and Health Science, Dept of Molecular Medicine, Auckland, New Zealand
A role for alpha4 and beta7 Integrins in mediating Leucocyte entry into the Central Nervous System in the Multiple Sclerosis (MS)-like disease Experimental AutoImmune EncephaloMyelitis (EAE) has been demonstrated.
However, the individual contributions of their respective Ligands Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1) and E-Cadherin expressed on the Blood-Brain Barrier has not been determined.
In the present paper, it is shown that an AntiBody directed against MAdCAM-1, the preferential Ligand for 4ß7, effectively prevented the development of a Progressive, Non-Remitting, form of EAE, actively induced by injection of Myelin Oligodendrocyte Glycoprotein peptide (MOG35-55) AutoAntigen.
Combinational treatment with both anti-MAdCAM-1, VCAM-1, and InterCellular Adhesion Molecule-1 (ICAM-1) (Ligand for Integrin Lymphocyte Function-Associated Antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 AntiBody alone.
However, neither MAdCAM-1 monotherapy, nor combinational AntiBody blockade was preventative when administered late in the course of disease progression.
In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS.
Critically, AntiVascular Addressin therapy must be given early in the course of disease prior to the establishment of irreversible damage if it is to be effective, as a single treatment modality.
No Evidence For Generation Of Th-2-Like MBP-Specific T-Cell Lines By Blockade Of The Costimulatory Molecule B7-1
Scand J Immunol 2000 Nov;52(5):510-4
Dept ofNeurology, Charite, Berlin, Germany
PMID# 11119251; UI# 20569717
The T-helper-1 (Th-1)/T helper-2 (Th-2) paradigm is relevant for the PathoGenesis and therapy of Multiple Sclerosis. In Experimental AutoImmune EncephaloMyelitis, a shift towards a Th-2 Immune Response serves as treatment of the disease.
In the human Immune System, the factors which determine and modulate the differentiation of CD4+ T Cells into the Th-1 or Th-2 phenotype have yet to be elucidated completely.
Here, the split-well approach was used to analyze costimulatory requirements for the generation of Myelin Basic Protein-specific T-Cell subsets considered to play a major role in the PathoGenesis of Multiple Sclerosis.
Myelin Basic Protein-specific T-Cell lines were isolated from peripheral blood cells of healthy individuals in the presence or absence of a blockade of the costimulatory molecule B7-1, previously reported to be involved in the development of Th-1 Cells.
T-Helper type was determined by the Interferon/InterLeukin ratio. Blockade of B7-1 did not increase the number of Th2-like Myelin Basic Protein-specific T-Cell lines.
Thus, these data show no evidence for an influence of B7-1 blockade on the development of human Myelin Basic Protein-specific T-Cell subsets.
These results have to be taken into account when discussing whether AntiBody-mediated B7-1 blockade might be a suitable therapy in Multiple Sclerosis, as demonstrated in Experimental AutoImmune EncephaloMyelitis.
Seasonal Patterns In Optic Neuritis And Multiple Sclerosis: A Meta-Analysis
Jin Y, de Pedro-Cuesta J, Soderstrom M, Stawiarz L, Link H
J Neurol Sci 2000 Dec 1;181(1-2):56-64
Karolinska Institute, Huddinge Univ Hospital, NeuroEpidemiology Unit, S-141 86, Huddinge, Sweden
To quantify and characterize seasonal variation in Monosymptomatic Optic Neuritis (MON) onsets, Multiple Sclerosis (MS) onsets and MS Exacerbations (MSE), a meta-analysis was performed.
Using established methods and pooling weighted information obtained from nine reports on MON, six reports on MS onsets and nine reports on MSE, which fulfilled specific criteria for report quality and data homogeneity.
The results suggested that MON, MS onsets and MSE in the Northern Hemisphere present a similar pattern with highest frequencies in Spring and lowest in Winter.
These differences were highest for MS onsets, 45% with 95% CI 36-55%, and lowest for MSE, 10% with 95% CI 7-13%, statistically significant and robust, insensitive to an alternative seasonal definition, not unduly influenced by any single primary study, and supported by fail-safe N calculations.
Random variation, misclassification and publication bias were less likely to account for the reported generalized seasonal patterns.
Myelin Oligodendrocyte Glycoprotein (MOG): A Model For AntiBody-Mediated DeMyelination In EAE And Multiple Sclerosis
Stefferl A, Brehm U, Linington C
J Neural Transm Suppl 2000;(58):123-33
Max-Planck-Institute for NeuroBiology, Planegg-Martinsried, Federal Republic of Germany
PMID# 11128602; UI# 21011149
The Myelin Oligodendrocyte Glycoprotein (MOG) is a major target for AutoAntiBody mediated DeMyelination in Experimental AutoImmune EncephaloMyelitis (EAE).
In the current review we discuss the Epitope specificity of this AntiBody response, in particular evidence suggesting that pathogenic Anti-MOG AntiBodies are preferentially directed against conformation-dependent Epitopes present on the ExtraCellular ImmunoGlobulin domain of the protein.
Surprisingly, recent data suggest that this AutoImmune response is in part regulated by polymorphisms in the MOG Gene itself, an observation that may have important implications for the Genetic and Immunological stratification of patients with Multiple Sclerosis.
Preferential Recognition Of TCR Hypervariable Regions By Human Anti-Idiotypic T-Cells Induced By T-Cell Vaccination
Zang YC, Hong J, Rivera VM, Killian J, Zhang JZ
J Immunol 2000 Apr 15;164(8):4011-7
Multiple Sclerosis Research Laboratory, Dept of Neurology and Baylor-Methodist Multiple Sclerosis Center, Dept of Microbiology and Immunology, and Neurology Research Laboratory, Veterans Affairs Medical Center, Baylor College
PMID#10754292; UI# 20219233
T-Cell responses to Myelin Basic Protein (MBP) are potentially involved in the PathoGenesis of Multiple Sclerosis (MS).
Immunization with irradiated MBP-reactive T-Cells (T-Cell Vaccination) induces anti-idiotypic T-Cell responses that suppress circulating MBP-reactive T-Cells.
This T-Cell-T-Cell interaction is thought to involve the recognition of TCR expressed on target T-Cells.
The study was undertaken to define the idiotypic determinants responsible for triggering CD8+ CytoToxic anti-idiotypic T-Cell responses by T-Cell vaccination in patients with MS.
A panel of 9-mer synthetic TCR Peptides corresponding to Complementarity-determining region 2 (CDR2) and CDR3 of the immunizing MBP-reactive T-Cell clones were used to isolate anti-idiotypic T-Cell lines from immunized MS patients.
The resulting TCR-specific T-Cell lines expressed exclusively the CD8+ phenotype and recognized preferentially the CDR3 Peptides. CDR3-specific T-Cell lines were found to Lyze specifically autologous immunizing MBP-reactive T-Cell clones.
The findings suggest that CDR3-specific T-Cells represented anti-idiotypic T-Cell population induced by T-Cell Vaccination.
In contrast, the CDR2 Peptides were less Immunogenic and contained cryptic determinants as the CDR2-specific T-Cell lines did not recognize autologous immunizing T-Cell clones from which the Peptide sequence was derived.
The study has important implications in our understanding of in vivo idiotypic regulation of AutoImmune T-Cells and the regulatory mechanism underlying T-Cell Vaccination.