DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury

Jianyi Wang, Qing Ye, Jing Xu, Gil Benedek, Haiyue Zhang, Yuanyuan Yang, Huan Liu, Roberto Meza-Romero, Arthur Vandenbark, Halina Offner, Yanqin Gao

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalTranslational Stroke Research
DOIs
Publication statusAccepted/In press - Dec 17 2016

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Keywords

  • DRα1-MOG-35-55
  • Inflammation
  • Microglia/macrophage
  • Stroke
  • T lymphocytes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Wang, J., Ye, Q., Xu, J., Benedek, G., Zhang, H., Yang, Y., ... Gao, Y. (Accepted/In press). DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury. Translational Stroke Research, 1-10. https://doi.org/10.1007/s12975-016-0514-2