ABSTRACT
Glatiramer acetate (GA) is an immunomodulator approved for therapy of relapsing-remitting multiple sclerosis (RRMS), but recent findings indicate that it may also have additional, neurotrophic effects. Here, we found that supernatants from human GA-reactive T lymphocytes potentiated oligodendrocyte numbers in rodent and human oligodendrocyte progenitor (OPC) cultures. Effects of Th2-polarized lines were stronger than Th1-polarized cells. Microarray and ELISA analyses revealed that neurotrophic factors induced in Th2- and Th1-polarized GA-reactive lines included IGF-2 and BMP-7 respectively, and functional studies confirmed IGF-2 as trophic for OPCs. Our results support the concept that GA therapy may result in supportive effects on oligodendrocytes in RRMS patients.
Subject(s)
Adjuvants, Immunologic/physiology , Insulin-Like Growth Factor II/physiology , Oligodendroglia/immunology , Peptides/physiology , Stem Cells/immunology , Stem Cells/physiology , Th2 Cells/immunology , Adjuvants, Immunologic/therapeutic use , Animals , Cell Line, Tumor , Cell Lineage/immunology , Cell Proliferation/drug effects , Cells, Cultured , Glatiramer Acetate , Humans , Lymphocyte Count/methods , Mice , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/immunology , Multiple Sclerosis, Relapsing-Remitting/pathology , Oligodendroglia/cytology , Oligodendroglia/drug effects , Peptides/therapeutic use , Stem Cells/cytology , Stem Cells/drug effects , Th2 Cells/cytology , Th2 Cells/drug effectsABSTRACT
Brain-reactive autoantibodies (BRAA) are thought to play an important role in central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE). Previous studies have shown the existence of BRAA in human and murine SLE. This study was undertaken to establish and characterize the presence of autoantibody binding to brain of autoimmune mice. Laser confocal microscopy was performed on frozen brain sections to detect the presence of immunoglobulin (Ig) in the brain of MRL/lpr and BXSB mice and compare that to control strains of MRL/mp and C57BL/6 mice. There was a dramatic increase in fluorescence in the brains of MRL/lpr and BXSB at 4 months of age. There was little or no Ig detected in the brains of control mice. This increase in presence of Ig in the autoimmune mouse brain was paralleled by an increase in the serum titers of BRAA and anti-DNA autoantibodies as determined by ELISA. These studies provide another link between the existence of brain-reactive autoantibodies and altered CNS functioning.