myelin-oligodendrocyte-glycoprotein-(35-55) and Central-Nervous-System-Diseases

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell-mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1

Topics: Animals; Animals, Newborn; Brain; Calcium-Binding Proteins; Cells, Cultured; Central Nervous System Diseases; Disease Models, Animal; DNA-Binding Proteins; Endonucleases; Female; Freund's Adjuvant; Gene Expression; Humans; Inflammation; Lipopolysaccharides; Macaca mulatta; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Microglia; Myelin-Oligodendrocyte Glycoprotein; Nerve Tissue Proteins; Peptide Fragments

DRα1-mouse(m)MOG-35-55, a novel construct developed in our laboratory as a simpler and potentially less immunogenic alternative to two-domain class II constructs, was shown previously to target the MIF/CD74 pathway and to reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in DR*1501-Tg mice in a manner similar to the parent DR2β1-containing construct.. In order to determine whether DRα1-mMOG-35-55 could treat EAE in major histocompatibility complex (MHC)-mismatched mice and to evaluate the treatment effect on central nervous system (CNS) inflammation, C57BL/6 mice were treated with DRα1-mMOG-35-55. In addition, gene expression profile was analyzed in spinal cords of EAE DR*1501-Tg mice that were treated with DRα1-mMOG-35-55.. We here demonstrate that DRα1-mMOG-35-55 could effectively treat EAE in MHC-mismatched C57BL/6 mice by reducing CNS inflammation, potentially mediated in part through an increased frequency of M2 monocytes in the spinal cord. Microarray analysis of spinal cord tissue from DRα1-mMOG-35-55-treated vs. vehicle control mice with EAE revealed decreased expression of a large number of pro-inflammatory genes including CD74, NLRP3, and IL-1β and increased expression of genes involved in myelin repair (MBP) and neuroregeneration (HUWE1).. These findings indicate that the DRα1-mMOG-35-55 construct retains therapeutic, anti-inflammatory, and neuroprotective activities during treatment of EAE across MHC disparate barriers.

Topics: Animals; CD11 Antigens; Cell Count; Cell Survival; Central Nervous System Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; HLA-DR alpha-Chains; Inflammation; Lectins, C-Type; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Nerve Regeneration; Neuroprotection; Neuroprotective Agents; Peptide Fragments; Receptors, Cell Surface