Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice

Suzan Dziennis, Sarah Mader, Kozaburo Akiyoshi, Xuefang Ren, Patricia Ayala, Gregory G. Burrows, Arthur Vandenbark, Paco S. Herson, Patricia D. Hurn, Halina Offner

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)123-133
Number of pages11
JournalMetabolic Brain Disease
Volume26
Issue number2
DOIs
StatePublished - Jun 2011

Fingerprint

T-cells
Middle Cerebral Artery Infarction
T-Cell Antigen Receptor
Brain
Ligands
T-Lymphocytes
Blood
Spleen
Lymph Nodes
Stroke
Chemical activation
Myelin-Oligodendrocyte Glycoprotein
Euthanasia
Chemokine Receptors
Encephalitis
Therapeutics
Myelin Sheath
Immunosuppression
Reperfusion
Atrophy

Keywords

  • Cerebral ischemia
  • Inflammation
  • Neuroprotection
  • T-cells
  • Therapeutic

ASJC Scopus subject areas

  • Clinical Neurology
  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. / Dziennis, Suzan; Mader, Sarah; Akiyoshi, Kozaburo; Ren, Xuefang; Ayala, Patricia; Burrows, Gregory G.; Vandenbark, Arthur; Herson, Paco S.; Hurn, Patricia D.; Offner, Halina.

In: Metabolic Brain Disease, Vol. 26, No. 2, 06.2011, p. 123-133.

Research output: Contribution to journalArticle

Dziennis, Suzan ; Mader, Sarah ; Akiyoshi, Kozaburo ; Ren, Xuefang ; Ayala, Patricia ; Burrows, Gregory G. ; Vandenbark, Arthur ; Herson, Paco S. ; Hurn, Patricia D. ; Offner, Halina. / Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. In: Metabolic Brain Disease. 2011 ; Vol. 26, No. 2. pp. 123-133.
@article{a871f0c3af4348e8a74ea50ef6cc13d7,
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.",
keywords = "Cerebral ischemia, Inflammation, Neuroprotection, T-cells, Therapeutic",
author = "Suzan Dziennis and Sarah Mader and Kozaburo Akiyoshi and Xuefang Ren and Patricia Ayala and Burrows, {Gregory G.} and Arthur Vandenbark and Herson, {Paco S.} and Hurn, {Patricia D.} and Halina Offner",
year = "2011",
month = "6",
doi = "10.1007/s11011-011-9241-2",
language = "English (US)",
volume = "26",
pages = "123--133",
journal = "Metabolic Brain Disease",
issn = "0885-7490",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice

AU - Dziennis, Suzan

AU - Mader, Sarah

AU - Akiyoshi, Kozaburo

AU - Ren, Xuefang

AU - Ayala, Patricia

AU - Burrows, Gregory G.

AU - Vandenbark, Arthur

AU - Herson, Paco S.

AU - Hurn, Patricia D.

AU - Offner, Halina

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

KW - Cerebral ischemia

KW - Inflammation

KW - Neuroprotection

KW - T-cells

KW - Therapeutic

UR - http://www.scopus.com/inward/record.url?scp=79959373208&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959373208&partnerID=8YFLogxK

U2 - 10.1007/s11011-011-9241-2

DO - 10.1007/s11011-011-9241-2

M3 - Article

VL - 26

SP - 123

EP - 133

JO - Metabolic Brain Disease

JF - Metabolic Brain Disease

SN - 0885-7490

IS - 2

ER -