Sheetal Bodhankar1, Yingxin Chen1, Andrew Lapato1, Abby L Dotson1, Jianming Wang1, Arthur A Vandenbark1, Julie A Saugstad1, Halina Offner2. 1. From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland. 2. From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland. offnerva@ohsu.edu.
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.
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-deficientmice. These results provide strong support for the use of available humanized anti-PD-L1 antibodies for treatment of humanstroke subjects.
Authors: Jason M Schenkel; Rebecca H Herbst; David Canner; Amy Li; Michelle Hillman; Sean-Luc Shanahan; Grace Gibbons; Olivia C Smith; Jonathan Y Kim; Peter Westcott; William L Hwang; William A Freed-Pastor; George Eng; Michael S Cuoco; Patricia Rogers; Jin K Park; Megan L Burger; Orit Rozenblatt-Rosen; Le Cong; Kristen E Pauken; Aviv Regev; Tyler Jacks Journal: Immunity Date: 2021-09-16 Impact factor: 43.474