TY - JOUR
T1 - DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury
AU - Wang, Jianyi
AU - Ye, Qing
AU - Xu, Jing
AU - Benedek, Gil
AU - Zhang, Haiyue
AU - Yang, Yuanyuan
AU - Liu, Huan
AU - Meza-Romero, Roberto
AU - Vandenbark, Arthur A.
AU - Offner, Halina
AU - Gao, Yanqin
N1 - Funding Information:
This work was supported by the NIH/National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS075887 (HO) and R01NS076013 (HO) 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.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - DRα1-MOG-35-55
KW - Inflammation
KW - Microglia/macrophage
KW - Stroke
KW - T lymphocytes
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U2 - 10.1007/s12975-016-0514-2
DO - 10.1007/s12975-016-0514-2
M3 - Article
C2 - 27988839
AN - SCOPUS:85006365068
VL - 8
JO - Translational Stroke Research
JF - Translational Stroke Research
SN - 1868-4483
IS - 3
ER -