Stangel M, Compston A, Scolding NJ
J NeuroImmunol 2000 Mar 1;103(2):195-201
Univ of Cambridge, Neurology Unit, Addenbrooke's Hospital, UK
PMID# 10696915; UI# 20159988
High-dose IntraVenous ImmunoGlobulin (IVIg) treatment has become a promising Immune therapy that can modulate the Immune System at several levels, including the Complement Cascade.
In relation to Inflammatory DeMyelinating Disease, there is some clinical evidence for the suppression of disease activity by IVIG, while a role in promoting ReMyelination after experimental Myelin damage has been described.
AntiBody and Complement deposition have been implicated in the Immune attack in some cases of Multiple Sclerosis (MS), and to investigate the mechanisms of action of IVIg, we studied the effect of IVIg using the model of Complement-mediated Cell Injury on Oligodendroglia in vitro.
There was no effect on direct Complement Lysis of the Oligodendroglial Cell Line CG4, but AntiBody-dependent Complement damage was inhibited in a dose-dependent manner by IVIg.
These results were confirmed with primary cultures of Oligodendrocyte Precursor Cells (OPC) and Oligodendrocytes.
The addition of excess C1, C3, and C4 did not influence the inhibitory effect of IVIG, implying that binding of these Complement components does not play a role, in contrast to other experimental models of Complement damage.
F(ab')2 ImmunoGlobulin fragments were at least partially responsible for the effect.
We conclude that IVIg may be protective in AntiBody-mediated Complement Injury of Oligodendrocytes and their Progenitors, and that this effect is likely to be mediated via AntiBody binding, rather than interference with Complement activation.
Inhibition of inflammatory mechanisms, as opposed to a direct effect on ReMyelinating Cells, may underlie the role of IVIg in promoting Myelin repair in experimental models.
Nashold FE, Miller DJ, Hayes CE
J NeuroImmunol 2000 Mar 1;103(2):171-9
Univ of Wisconsin-Madison, Dept of BioChemistry, Madison, Wisconsin 53706, USA
PMID# 10696912; UI# 20159985
Sunlight, which is required for Vitamin D biosynthesis, may be protective in Multiple Sclerosis (MS), due to the ImmunoRegulatory Functions of 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the Hormonally active Vitamin D metabolite.
This hypothesis provided the impetus for the experiments reported here investigating mechanisms whereby 1,25-(OH)2D3 may inhibit murine Experimental AutoImmune EncephaloMyelitis (EAE).
Severe EAE was induced, 1,25-(OH)2D3 or mock treatment was administered, and clinical disease, HistoPathological Disease, and EncephalitoGenic Cells in the Central Nervous System (CNS) were analyzed within 24-72 h of the treatment.
The mock-treated mice remained paralyzed (stage 3 EAE) while most Hormone-treated animals regained the partial use of both hind limbs (stage 2 EAE) within 72 h of treatment.
A HistoPathological examination showed the Hormone-treated mice had a 50% decrease in White Matter and Meningeal Inflammation at 72 h post treatment.
A flow cytometric analysis of cell surface markers on Spinal Cord Cells recovered 24 h post treatment showed the mock-treated mice with EAE had about 7.0 +/- 2.3 million Mac-1+ Cells/Cord, whereas the Hormone-treated mice had about 2.1 +/- 2.6 million Mac-1+ Cells/Cord, which was not significantly different from the unmanipulated control mice.
Otherwise, the flow cytometric analysis detected no significant differences between the groups with respect to CD4+ or CD8+ T-Cells or B-Cells or Macrophages in draining Lymph Nodes or Spinal Cords.
These results are discussed with regard to possible fates for the 5 million Mac-1+ Cells that were rapidly lost from the inflamed CNS in the 1,25-(OH)2D3-treated mice, and the possible beneficial effect of Hormone treatment in resolving acute MS.
ß7 Integrins Contribute To DeMyelinating Disease Of The Central Nervous System
Kanwar JR, Harrison JE, Wang D, Leung E, Mueller W, Wagner N, Krissansen GW
J NeuroImmunol 2000 Mar 1;103(2):146-52
Univ of Auckland, School of Medicine and Health Science, Dept of Molecular Medicine, Auckland, New Zealand
PMID# 10696909; UI# 20159982
A role for 4 Integrins in different forms of the Multiple Sclerosis-like disease Experimental AutoImmune EncephaloMyelitis (EAE) has been demonstrated.
But, the individual contributions of 4ß1, 4ß7, and the related Eß7 Integrin have not been determined.
The P7 Integrins 4ß7 and Eß7 play a central role in Chronic Inflammation, mediating the trafficking, entry, and/or adhesion of Lymphocytes in the inflamed Pancreas and Gut.
And, their Ligands MAdCAM-1, VCAM-1 and E-Cadherin are expressed on Brain Endothelial Cells and/or on MicroVessels in the inflamed Central Nervous System.
Here, we show that an AntiBody directed against the ß7 subunit greatly attenuates a Non-Remitting form of EAE, induced by adoptive transfer of Myelin Oligodendrocyte peptide (MOG35-55)-stimulated T-Cells.
Combinational treatment with both anti-ß7 and 4 Integrin subunit AntiBodies led to more rapid and complete remission than that obtained with anti-4 AntiBody alone.
Potentially implicating a role for Eß7 in disease progression.
Remission correlated with the down-regulation of the Vascular Addressins VCAM-1. MAdCAM-1, and ICAM-1 on Cerebral blood vessels.
Attenuated forms of disease were induced by adoptive transfer of either wild-type EncephalitoGenic T-Cells to ß7-deficient Gene knockout mice, or of ß7-/-EncephalitoGenic T-Cells to wild-type recipients.
The former finding indicates that ß7 + ve recruited cells contribute to disease progression.
Thus 4ß1, 4ß7, and Eß7 Integrins may all play a contributory role in the Progression of Chronic Forms of DeMyelinating Disease.
And, together with their Ligands could represent potential targets for improved treatment of some forms of Multiple Sclerosis.