Journal
STROKE
Volume 46, Issue 10, Pages 2926-2934Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.115.010592
Keywords
anti-PD-L1 antibody therapy; interleukin-10; middle cerebral artery occlusion; reperfusion; stroke
Categories
Funding
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [1RO1 NS075887, 1RO1 NS047661]
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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 g 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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