Metabolic Brain Disease

, Volume 29, Issue 1, pp 37–45 | Cite as

A novel HLA-DRα1-MOG-35-55 construct treats experimental stroke

  • Gil Benedek
  • Wenbin Zhu
  • Nicole Libal
  • Amanda Casper
  • Xiaolin Yu
  • Roberto Meza-Romero
  • Arthur A. Vandenbark
  • Nabil J. Alkayed
  • Halina Offner
Original Paper

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.

Keywords

Stroke Inflammation Immunotherapy Recombinant T-cell receptor Ligand MHC class II invariant chain 

Abbreviations

MCAO

Middle cerebral artery occlusion

RTL

Recombinant T-cell receptor ligand

MHC

Major histocompatibility complex

Supplementary material

11011_2013_9440_MOESM1_ESM.pdf (46 kb)
ESM 1(PDF 46 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gil Benedek
    • 1
    • 3
  • Wenbin Zhu
    • 2
  • Nicole Libal
    • 2
  • Amanda Casper
    • 2
  • Xiaolin Yu
    • 1
    • 3
  • Roberto Meza-Romero
    • 1
    • 3
  • Arthur A. Vandenbark
    • 1
    • 3
    • 4
  • Nabil J. Alkayed
    • 2
  • Halina Offner
    • 1
    • 2
    • 3
  1. 1.Neuroimmunology Research, R&D-31Portland Veterans Affairs Medical CenterPortlandUSA
  2. 2.Department of Anesthesiology and Perioperative MedicineOregon Health & Science UniversityPortlandUSA
  3. 3.Department of NeurologyOregon Health & Science UniversityPortlandUSA
  4. 4.Department of Molecular Microbiology & ImmunologyOregon Health & Science UniversityPortlandUSA

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