1. HLA-DRα1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection.
- Author
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Benedek G, Meza-Romero R, Jordan K, Keenlyside L, Offner H, and Vandenbark AA
- Subjects
- Animals, CD11 Antigens metabolism, Cell Count, Cell Survival drug effects, Central Nervous System Diseases pathology, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental pathology, HLA-DR alpha-Chains analysis, HLA-DR alpha-Chains pharmacology, Inflammation pathology, Lectins, C-Type metabolism, Macrophages drug effects, Macrophages immunology, Male, Mannose Receptor, Mannose-Binding Lectins metabolism, Mice, Mice, Inbred C57BL, Myelin-Oligodendrocyte Glycoprotein analysis, Myelin-Oligodendrocyte Glycoprotein pharmacology, Nerve Regeneration drug effects, Neuroprotection drug effects, Neuroprotective Agents analysis, Neuroprotective Agents pharmacology, Peptide Fragments analysis, Peptide Fragments pharmacology, Peptide Fragments therapeutic use, Receptors, Cell Surface metabolism, Central Nervous System Diseases drug therapy, Encephalomyelitis, Autoimmune, Experimental drug therapy, HLA-DR alpha-Chains therapeutic use, Inflammation drug therapy, Macrophages pathology, Myelin-Oligodendrocyte Glycoprotein therapeutic use, Neuroprotective Agents therapeutic use
- Abstract
Background: 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., Methods: 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., Results: 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)., Conclusion: 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.
- Published
- 2015
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