http://stroke.ahajournals.org/content/46/10/2926.abstract?sid=59388841-3a8f-40e1-8b7d-319e6d306b95
- Sheetal Bodhankar, PhD*;
- Yingxin Chen, MD*;
- Andrew Lapato, BS;
- Abby L. Dotson, PhD;
- Jianming Wang, MD;
- Arthur A. Vandenbark, PhD;
- Julie A. Saugstad, PhD;
- Halina Offner, DrMed
+ Author Affiliations
- Correspondence to Halina Offner, DrMed, Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR 97239. E-mail offnerva@ohsu.edu
-
↵* Drs Bodhankar and Chen contributed equally.
Abstract
Background and Purpose—Both
pathogenic and regulatory immune processes are involved in the middle
cerebral artery occlusion (MCAO) model of experimental
stroke, including interactions involving the
programmed death 1 (PD-1) receptor and its 2 ligands, PD-L1 and PD-L2.
Although
PD-1 reduced stroke severity, PD-L1 and PD-L2
appeared to play pathogenic roles, suggesting the use of anti-PD-L
monoclonal
antibody therapy for MCAO.
Methods—Male
C57BL/6 mice were treated with a single dose of anti-PD-L1 monoclonal
antibody 4 hours after MCAO and evaluated for clinical,
histological and immunologic changes after 96
hours of reperfusion.
Results—Blockade of
the PD-L1 checkpoint using a single injection of 200 μg anti-PD-L1
monoclonal antibody given intravenously 4 hours
after occlusion significantly reduced MCAO
infarct volumes and improved neurological outcomes after 96 hours of
reperfusion.
Treatment partially reversed splenic atrophy
and decreased central nervous system infiltrating immune cells
concomitant with
enhanced appearance of CD8+ regulatory T cells in the lesioned central nervous system hemisphere.
Conclusions—This
study demonstrates for the first time the beneficial therapeutic effects
of PD-L1 checkpoint blockade on MCAO, thus validating
proposed mechanisms obtained in our previous
studies using PD-1- and PD-L-deficient mice. These results provide
strong support
for the use of available humanized anti-PD-L1
antibodies for treatment of human stroke subjects.
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