title: A novel HLA-DRα1-MOG-35-55 construct treats experimental stroke.
abstract: Chemoattraction of leukocytes into the brain after induction of middle cerebral artery occlusion (MCAO) increases the lesion size and worsens disease outcome. Our previous studies demonstrated that partial MHC class II constructs can reverse this process. However, the potential application of pMHC to human stroke is limited by the need to rapidly match recipient MHC class II with the β1 domain of the pMHC construct. We designed a novel recombinant protein comprised of the HLA-DRα1 domain linked to MOG-35-55 peptide but lacking the β1 domain found in pMHC and treated MCAO after 4 h reperfusion in humanized DR2 mice. Infarct volumes were quantified after 96 h reperfusion and immune cells from the periphery and CNS were evaluated for expression of CD74 and other cell surface, cytokine and pathway markers. This study demonstrates that four daily treatments with DRα1-MOG-35-55 reduced infarct size by 40 % in the cortex, striatum and hemisphere, inhibited the migration of activated CD11b+CD45high cells from the periphery to the brain and reversed splenic atrophy. Furthermore, DRα1-MOG-35-55 bound to CD74 on monocytes and blocked both binding and downstream signaling of macrophage migration inhibition factor (MIF) that may play a key role in infarct development. The novel DRα1-MOG-35-55 construct is highly therapeutic in experimental stroke and could be given to all patients at least 4 h after stroke onset without the need for tissue typing due to universal expression of DRα1 in humans.
authors.forename: Gil
authors.initials: G
authors.lastname: Benedek
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhu
authors.forename: Nicole
authors.initials: N
authors.lastname: Libal
authors.forename: Amanda
authors.initials: A
authors.lastname: Casper
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yu
authors.forename: Roberto
authors.initials: R
authors.lastname: Meza-Romero
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D001284:Atrophy; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D059910:HLA-B15 Antigen / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000627:therapeutic use*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; C483536:HLA-B*15:02 antigen; D059910:HLA-B15 Antigen; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C045084:invariant chain; C445081:myelin oligodendrocyte glycoprotein (35-55)