Alexander E. Merkler, MD

Bodhankar S, Chen Y, Lapato A, Dotson AL, Wang J, Vandenbark AA, et al. PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation. Stroke. 2015
Treatment options for acute ischemic stroke are limited. Although tPA and endovascular clot retrieval are beneficial, they are time-limited treatments which are not available to the majority of patients with stroke. Although targeting post-stroke inflammation is not a new concept, new advances in immunotherapy may lead to huge advances in post-stroke therapy.

Post-stroke inflammation begins with release of reactive oxygen species, which may trigger a cascade of activating complement, platelets, and endothelial cells leading to further neurological injury. Reperfusion, one of the goals of early acute ischemic stroke treatment, may also enhance the inflammatory process and lead to additional injury to brain tissue.

Dr. Bodhankar et al assess a new immunotherapy aimed at reducing the inflammation related to post-stroke reperfusion injury. The current study builds on their prior research, which showed that Programmed Death 1 (PD-1) receptor and its two ligands (PD-L1 and PD-L2) regulate the function of inflammatory immune cells and that mice deficient in the PD-L1 ligand had smaller infarct volumes when exposed to middle cerebral artery occlusion (MCAO). Based on the potentially pathogenic role of PD-L1 ligand, in the current study, the authors assess the effectiveness of blocking PD-L1 using a monoclonal antibody and assess outcomes via measuring stroke infarct volume and neurologic function.

Mice were exposed to transient focal ischemia via 1 hour of MCAO in the right brain hemisphere followed by 96h of reperfusion. Mice were given either monoclonal anti-PD-L1 antibody or an isotype matched control 4 hours following MCAO. First, the results support the theory that stroke and/or reperfusion leads to inflammation as both groups of mice had elevated leukocyte counts in the affected hemisphere, but not in the unaffected hemisphere. Second, as compared to mice treated with the control drug, mice treated with the monoclonal anti-PD-L1 antibody had a reduced number of pro-inflammatory cells in the ischemic hemisphere, supporting the anti-inflammatory effect of the antibody. Third, and most importantly, at 96 hours, infarct volume and neurological deficit were significantly reduced in mice that received the monocloncal antibody as compared to the matched controls. Noteworthy, however, is that 5 of the 73 monocloncal antibody treated mice developed severe hemorrhage and were excluded from the analysis while not of the control mice developed this complication.

Overall, the study provides exciting new vigor to post-stroke immunotherapy treatment. Blocking PD-L1 may be a viable treatment strategy in reducing post-stroke inflammation and thereby stroke infarct volume and neurological injury.