title: DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury.
abstract: Stroke induces a catastrophic immune response that involves the global activation of peripheral leukocytes, especially T cells. The human leukocyte antigen-DRα1 domain linked to MOG-35-55 peptide (DRα1-MOG-35-55) is a partial major histocompatibility complex (MHC) class II construct which can inhibit neuroantigen-specific T cells and block binding of the cytokine/chemokine macrophage migration inhibitory factor (MIF) to its CD74 receptor on monocytes and macrophages. Here, we evaluated the therapeutic effect of DRα1-MOG-35-55 in a mouse model of permanent distal middle cerebral artery occlusion (dMCAO). DRα1-MOG-35-55 was administered to WT C57BL/6 mice by subcutaneous injection starting 4 h after the onset of ischemia followed by three daily injections. We demonstrated that DRα1-MOG-35-55 post treatment significantly reduced brain infarct volume, improved functional outcomes, and inhibited the accumulation of CD4+and CD8+T cells and expression of pro-inflammatory cytokines in the ischemic brain 96 h after dMCAO. In addition, DRα1-MOG-35-55 treatment shifted microglia/macrophages in the ischemic brain to a beneficial M2 phenotype without changing their total numbers in the brain or blood. This study demonstrates for the first time the therapeutic efficacy of the DRα1-MOG-35-55 construct in dMCAO across MHC class II barriers in C57BL/6 mice. This MHC-independent effect obviates the need for tissue typing and will thus greatly expedite treatment with DRα1-MOG-35-55 in human stroke subjects. Taken together, our findings suggest that DRα1-MOG-35-55 treatment may reduce ischemic brain injury by regulating post-stroke immune responses in the brain and the periphery.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA.|Xiangya Third Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA.|Department of Anesthesiology, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, 20031, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR, 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Benedek
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA.|Xiangya Third Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA.|Xiangya Third Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA.|Xiangya Third Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR, 97239, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Meza-Romero
authors.affiliation: Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR, 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR, USA.|Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.affiliation: Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR, 97239, USA. offnerva@ohsu.edu.|Department of Neurology, Oregon Health & Science University, Portland, OR, USA. offnerva@ohsu.edu.|Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA. offnerva@ohsu.edu.
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, SBST 506, Pittsburgh, PA, 15213, USA. yag38@pitt.edu.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D027963:Chloride-Bicarbonate Antiporters / Q000494:pharmacology*; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy*; D000076988:Sulfate Transporters
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C081011:SLC26A3 protein, human; D000076988:Sulfate Transporters; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: DRα1-MOG-35-55; Inflammation; Microglia/macrophage; Stroke; T lymphocytes