Characterization of the Effects of IVIg on CNS Inflammation Leading to Non-Classical Disease in a Relapsing Remitting Model of EAE

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: 1) 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. 2) 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 3) 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