title: Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice.
abstract: Stroke induces a biphasic effect on the peripheral immune response that involves early activation of peripheral leukocytes followed by severe immunosuppression and atrophy of the spleen. Peripheral immune cells, including T lymphocytes, migrate to the brain and exacerbate the developing infarct. Recombinant T-cell receptor (TCR) Ligand (RTL)551 is designed as a partial TCR agonist for myelin oligodendrocyte glycoprotein (MOG)-reactive T cells and has demonstrated the capacity to limit infarct volume and inflammation in brain when administered to mice undergoing middle cerebral artery occlusion (MCAO). The goal of this study was to determine if RTL551 could retain protection when given within the therapeutically relevant 4 h time window currently in clinical practice for stroke patients. RTL551 was administered subcutaneously 4 h after MCAO, with repeated doses every 24 h until the time of euthanasia. Cell numbers were assessed in the brain, blood, spleen and lymph nodes and infarct size was measured after 24 and 96 h reperfusion. RTL551 reduced infarct size in both cortex and striatum at 24 h and in cortex at 96 h after MCAO and inhibited the accumulation of inflammatory cells in brain at both time points. At 24 h post-MCAO, RTL551 reduced the frequency of the activation marker, CD44, on T-cells in blood and in the ischemic hemisphere. Moreover, RTL551 reduced expression of the chemokine receptors, CCR5 in lymph nodes and spleen, and CCR7 in the blood and lymph nodes. These data demonstrate effective treatment of experimental stroke with RTL551 within a therapeutically relevant 4 h time window through immune regulation of myelin-reactive inflammatory T-cells.
authors.affiliation: Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, USA.
authors.forename: Suzan
authors.initials: S
authors.lastname: Dziennis
authors.forename: Sarah
authors.initials: S
authors.lastname: Mader
authors.forename: Kozaburo
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Xuefang
authors.initials: X
authors.lastname: Ren
authors.forename: Patricia
authors.initials: P
authors.lastname: Ayala
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Halina A
authors.initials: HA
authors.lastname: Offner
mesh_terms: D000818:Animals; D001769:Blood / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000819:agonists / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000276:immunology; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018960:Hyaluronan Receptors; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C542327:RTL551 protein; D011948:Receptors, Antigen, T-Cell; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D011993:Recombinant Fusion Proteins