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

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An Erratum to this article was published on 06 March 2014

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.

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Abbreviations

MCAO:

Middle cerebral artery occlusion

RTL:

Recombinant T-cell receptor ligand

MHC:

Major histocompatibility complex

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Acknowledgments

The authors wish to thank Melissa S. Barber for assistance with manuscript submission. This work was supported by NIH Grants #NS076013 (STTR), and NS047661 and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Neuroimmunology Research, R&D-31, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR, 97239, USA

    Gil Benedek, Xiaolin Yu, Roberto Meza-Romero, Arthur A. Vandenbark & Halina Offner

  2. Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA

    Wenbin Zhu, Nicole Libal, Amanda Casper, Nabil J. Alkayed & Halina Offner

  3. Department of Neurology, Oregon Health & Science University, Portland, OR, USA

    Gil Benedek, Xiaolin Yu, Roberto Meza-Romero, Arthur A. Vandenbark & Halina Offner

  4. Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, USA

    Arthur A. Vandenbark

Authors
  1. Gil Benedek
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  2. Wenbin Zhu
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  3. Nicole Libal
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  4. Amanda Casper
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  5. Xiaolin Yu
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  6. Roberto Meza-Romero
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  7. Arthur A. Vandenbark
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  8. Nabil J. Alkayed
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  9. Halina Offner
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Corresponding author

Correspondence to Halina Offner.

Additional information

Gil Benedek and Wenbin Zhu contributed equally to this work.

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Benedek, G., Zhu, W., Libal, N. et al. A novel HLA-DRα1-MOG-35-55 construct treats experimental stroke. Metab Brain Dis 29, 37–45 (2014). https://doi.org/10.1007/s11011-013-9440-0

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