Publication: Characterization of the Effects of IVIg on CNS Inflammation Leading to Non-Classical Disease in a Relapsing Remitting Model of EAE
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Abstract
Intravenous Immunoglobulin (IVIg) is a complex therapeutic used in the treatment of multiple autoimmune and inflammatory diseases. The mechanism of action of IVIg is pleiotropic; there is increasing evidence that modulation of migration through the expression or function of selectins such as very late antigen-4 (VLA-4) may be central to therapeutic activity.
The impetus for the present studies arose from an unexpected and novel observation that was made while investigating IVIg treatment in a relapsing remitting (RR) model of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Specifically, treatment with IVIg led to a shift from classical ascending paralysis to a non-classical ataxic disease. Others have demonstrated that this change in phenotype reflects a shift in localization of inflammation from the spinal cord to the brain and brain stem in EAE. In line with recent reports showing that shifts from classical to non-classical disease phenotype is mediated by shifts in the relative abundance of T helper cells (Th1 and Th17 cells), we hypothesized our observation may reflect an effect of IVIg on VLA-4 mediated migration leading to differential localization of Th1 and Th17 cells to the CNS during inflammation.
In the process of investigating this hypothesis three key observations were made:
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There was a decrease in B cells in the CNS with IVIg treatment; we hypothesize the impacted B cells were regulatory B cells, based on the timing and context of their development.
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An increase in CD8+ cells was observed in the anterior CNS associated with increased inflammation and demyelination; this population is hypothesized to be the effector population involved in the observed disease phenotype
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We found evidence in the periphery suggesting IVIg has Th1 modulating activity that is overtly similar to anti-VLA-4 treatment in EAE reported previously by others.